17-Acetamido-4-azasteroid derivatives as androgen receptor modulators

ABSTRACT

Compounds of structural formula I are modulators of the androgen receptor (AR) in a tissue selective manner. They are useful as agonists of the androgen receptor in bone and/or muscle tissue while antagonizing the AR in the prostate of a male patient or in the uterus of a female patient. These compounds are therefore useful in the enhancement of weakened muscle tone and the treatment of conditions caused by androgen deficiency or which can be ameliorated by androgen administration, including osteoporosis, osteopenia, glucocorticoid-induced osteoporosis, periodontal disease, bone fracture, bone damage following bone reconstructive surgery, sarcopenia, frailty, aging skin, male hypogonadism, postmenopausal symptoms in women, atherosclerosis, hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and other hematopoietic disorders, inflammatory arthritis and joint repair, HIV-wasting, prostate cancer, cancer cachexia, Alzheimer&#39;s disease, muscular dystrophies, cognitive impairment, decreased libido, premature ovarian failure, and autoimmune disease, alone or in combination with other active agents.

FIELD OF THE EVICTION

The present invention relates to 17-acetamido-4-azasteroid derivatives,their synthesis, and their use as androgen receptor modulators. Moreparticularly, the compounds of the present invention aretissue-selective androgen receptor modulators (SARMs) and are therebyuseful for the treatment of conditions caused by androgen deficiency orwhich can be ameliorated by androgen administration, such asosteoporosis, periodontal disease, bone fracture, frailty, andsarcopenia. Additionally, the SARMs of the present invention can be usedto treat mental disorders associated with low testosterone, such asdepression, sexual dysfunction, and cognitive decline. SARMS, beingantagonists in specific tissues, are also useful in conditions whereelevated androgen tone or activity causes symptoms, such as benignprostate hyperplasia and sleep apnea

BACKGROUND OF THE INVENTION

The androgen receptor (AR) belongs to the superfamily of steroid/thyroidhormone nuclear receptors, whose other members include the estrogenreceptor, the progesterone receptor, the glucocorticoid receptor, andthe mineralocorticoid receptor. The AR is expressed in numerous tissuesof the body and is the receptor through which the physiological as wellas the pathophysiological effects of androgens, such as testosterone (T)and dihydrotestosterone (DHr), are mediated. Structurally, the AR iscomposed of three functional domains: the ligand binding domain (LBD),the DNA-binding domain, and amino-terminal domain. A compound that bindsto the AR and mimics the effects of an endogenous AR ligand is referredto as an AR agonist, whereas a compound that inhibits the effects of anendogenous AR ligand is termed an AR antagonist.

Androgen ligand binding to the AR induces a ligand/receptor complex,which, after translocation into the nucleus of the cell, binds toregulatory DNA sequences (referred to as androgen response elements)within the promoter or enhancer regions of the target genes present inthe nucleus. Other proteins termed cofactors are next recruited, whichbind to the receptor leading to gene transcription.

Androgen therapy has been to treat a variety of male disorders such asreproductive disorders and primary or secondary male hypogonadism.Moreover, a number of natural or synthetic AR agonists have beeninvestigated for the treatment of musculoskeletal disorders, such asbone disease, hematopoietic disorders, neuromuscular disease,rheumatological disease, wasting disease, and for hormone replacementtherapy (HRT), such as female androgen deficiency. In addition, ARantagonists, such as flutamide and bicalutamide, are used to treatprostate cancer. It would therefore be useful to have availablecompounds that can activate (“agonize”) the function of the AR in atissue-selective manner that would produce the desired osteo- andmyoanabolic effects of androgens without the negative androgenicproperties, such as virilization and repression of high densitylipoprotein cholesterol (HDL).

The beneficial effects of androgens on bone in postmenopausalosteoporosis were documented in recent studies using combinedtestosterone and estrogen administration [Hofbauer, et al., Eur. J.Edocrinol. 140: 271-286 (1999)]. In a large 2-year, double-blindcomparison study, oral conjugated estrogen (CEE) and methyltestosteronecombinations were demonstrated to be effective in promoting accrual ofbone mass in the spine and hip, while conjugated estrogen therapy aloneprevented bone loss [J. Reprod. Med., 44: 1012-1020 (1999)].

Additionally, there is evidence that hot flushes decrease in womentreated with CEE and methyltestosterone; however, 30% of the treatedwomen suffered from significant increases in acne and facial hair, acomplication of all current androgen pharmacotherapies [Watts, et al.,Obstet. Gynecol., 85: 529-537 (1995)]. It was also found that theaddition of methyltestosterone to CEE decreased HDL levels, as seen inother studies. Thus, the virilizing potential and effects on lipidprofile of current androgen therapies provide a rationale for developingtissue-selective androgen receptor agonists.

Androgens play an important role in bone metabolism in men [Anderson, etal., “Androgen supplementation in eugonadal men withosteoporosis—effects of six months of treatment on bone mineral densityand cardiovascular risk factors,” Bone, 18: 171-177 (1996)]. Even ineugonadal men with osteoporosis, the therapeutic response totestosterone treatment reveals that androgens exert importantosteoanabolic effects. Mean lumbar BMD increased from 0.799 gm/cm2 to0.839 g/cm2, in 5 to 6 months in response to 250 mg of testosteroneester administered intramuscularly. SARMs can thus be used to treatosteoporosis in men.

Androgen deficiency occurs in men with stage D prostate cancer(metastatic) who undergo androgen deprivation therapy (ADT). Endocrineorchiectomy is achieved by long acting GnRH agonists, while androgenreceptor blockade is implemented with AR antagonists. In response tohormonal deprivation, these men suffered from hot flushes, significantbone loss, weakness, and fatigue. In a pilot study of men with stage Dprostate cancer, osteopenia (50% vs. 38%) and osteoporosis (38% vs. 25%)were more common in men who had undergone ADT for greater than one yearthan the patients who did not undergo ADT [Wei, et al., Urology. 54:607-611 (1999)]. Lumbar spine BMD was significantly lower in men who hadundergone ADT. Thus tissue selective AR antagonists in the prostate thatlack antagonistic action in bone and muscle can be useful agents for thetreatment of prostate cancer, either alone or as an adjunct totraditional ADT [See also A. Stoch, et al., J. Clin. Endocrin. Metab.,86: 2787-2791 (2001)].

Tissue-selective AR antagonists can also treat polycystic ovariansyndrome in postmenopausal women. See C. A. Eagleson, et al.,“Polycystic ovarian syndrome: evidence that flutamide restoressensitivity of the gonadotropin-releasing hormone pulse generator toinhibition by estradiol and progesterone,” J. Clin. Endocrinol. Metab.,85: 4047-4052 (2000).

SARMs can also treat certain hematopoietic disorders as androgensstimulate renal hypertrophy and erythropoietin (EPO) production. Priorto the introduction of recombinant human EPO, androgens were employed totreat anemia caused by chronic renal failure. In addition, androgensincrease serum EPO levels in anemic patients with non-severe aplasticanemia and myelodysplastic syndromes. Treatment for anemia will requireselective action such as can be provided by SARMs.

SARMs can also have clinical value as an adjunct to the treatment ofobesity. This approach to lowering body fat is supported by publishedobservations that androgen administration reduced subcutaneous andvisceral fat in obese patients [J. C. Lovejoy, et al., “Oral anabolicsteroid treatment, but not parenteral androgen treatment, decreasesabdominal fat in obese, older men,” Int. J. Obesity, 19: 614-624(1995)], [J. C. Lovejoy, et al., “Exogenous Androgens Ifluence BodyComposition and Regional Body Fat Distribution in Obese PostmenopausalWomen—A Clinical Research Center Study,” J. Clin. Endocrinol. Metab.,81: 2198-2203 (1996)]. Therefore, SARMs devoid of unwanted androgeniceffects can be beneficial in the treatment of obesity.

Androgen receptor agonists can also have therapeutic value againstneurodegenerative diseases such as Alzheimer's disease (AD). The abilityof androgens to induce neuroprotection through the androgen receptor wasreported by J. Hammond, et al., “Testosterone-mediated neuroprotectionthrough the androgen receptor in human primary neurons,” J. Neurochem.,77: 1319-1326 (2001). Gouras et al. reported that testosterone reducessecretion of Alzheimer's β-amyloid peptides and can therefore be used inthe treatment of AD [(Proc. Nat. Acad. Sci., 97: 1202-1205 (2000)). Amechanism via inhibition of hyperphosphorylation of proteins implicatedin the progression AD has also been described [S. Papasozomenos,“Testosterone prevents the heat shock-induced over activation ofglycogen synthase kinase-3β but not of cyclin-dependent kinase 5 andc-Jun NH₂-terminal kinase and concomitantly abolisheshyperphosphorylation of r: Implications for Alzheimer's disease,” Proc.Nat. Acad. Sci., 99: 1140-1145 (2002)].

Androgen receptor agonists can also have a beneficial effect on muscletone and strength. Recent studies have demonstrated that “physiologicandrogen replacement in healthy, hypogonadal men is associated withsignificant gains in fat-free mass, muscle size and maximal voluntarystrength,” [S. Bhasin, et al., J. Endocrin., 170: 27-38 (2001)].

Androgen receptor modulators can be useful in treating decreased libidoin both men and women. Androgen deficiency in men is related todiminished libido. S. Howell et al., Br. J. Cancer, 82: 158-161. Lowandrogen levels contribute to the decline in sexual interest in manywomen during their later reproductive years. S. Davis, J. Clin.Endocrinol. Metab. 84: 1886-1891 (1999). In one study, circulating freetestosterone was positively correlated with sexual desire. Id. Inanother study, women with primary or secondary adrenal insufficiencywere provided physiological DHEA replacement (50 mg/day). Compared withwomen taking placebo, DHEA-administered women showed an increase in thefrequency of sexual thoughts, interest, and satisfaction. W. Arlt, etal., N Engl. J. Med. 341:1013-1020 (1999), see also, K. Miller, J. Clin.Endocrinol. Metab., 86: 2395-2401 (2001).

Additionally, androgen receptor modulators may also be useful intreating cognitive impairment. In a recent study, high-dose oralestrogen either alone or in combination with high-dose oralmethyltestosterone was given to postmenopausal women for a four-monthperiod. Cognitive tests were administered before and after thefour-month hormone treatment. The investigation found that womenreceiving a combination of estrogen (1.25 mg) and methyltestosterone(2.50 mg) maintained a steady level of performance on the BuildingMemory task, but the women receiving estrogen (1.25 mg) alone exhibiteddecreased performance. A. Wisniewski, Horm. Res. 58:150-155 (2002).

SUMMARY OF THE INVENTION

The present invention relates to compounds of structural formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, theiruses and pharmaceutical compostions.

These compounds are effective as androgen receptor agonists and areparticularly effective as SARMs. They are therefore useful for thetreatment of conditions caused by androgen deficiency or which can beameliorated by androgen administration.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

In this invention, we have identified compounds that function as SARMsusing a series of in vitro cell-assays that profile ligand mediatedactivation of AR, such as (i) N—C interaction, (ii) transcriptionalrepression, and (iii) transcriptional activation. SARM compounds in thisinvention, identified with the methods listed above, exhibit tissueselective AR agonism in vivo, i.e. agonism in bone (stimulation of boneformation in a rodent model of osteoporosis) and antagonism in prostate(minimal effects on prostate growth in castrated rodents and antagonismof prostate growth induced by AR agonists).

The compounds of the present invention identified as SARMs are useful totreat diseases or conditions caused by androgen deficiency which can beameliorated by androgen administration. Such compounds are ideal for thetreatment of osteoporosis in women and men as a monotherapy or incombination with inhibitors of bone resorption, such as bisphosphonates,estrogens, SERMs, cathepsin K inhibitors, αvβ3 integrin receptorantagonists, calcitonin, and proton pump inhibitors. They can also beused with agents that stimulate bone formation, such as parathyroidhormone or analogs thereof. The SARM compounds of the present inventioncan also be employed for treatment of prostate disease, such as prostatecancer and benign prostatic hyperplasia (BPH). Moreover, compounds ofthis invention exhibit minimal effects on skin (acne and facial hairgrowth) and can be useful for treatment of hirsutism. Additionally,compounds of this invention can stimulate muscle growth and can beuseful for treatment of sarcopenia and frailty. They can be employed toreduce visceral fat in the treatment of obesity. Moreover, compounds ofthis invention can exhibit androgen agonism in the central nervoussystem and can be useful to treat vasomotor symptoms (hot flush) and toincrease energy and libido. They can be used in the treatment ofAlzheimer's disease.

The compounds of the present invention can also be used in the treatmentof prostate cancer, either alone or as an adjunct to GnRHagonist/antagonist therapy, for their ability to restore bone, or as areplacement for antiandrogen therapy because of their ability toantagonize androgen in the prostate, and minimize bone depletion.Further, the compounds of the present invention can be used for theirability to restore bone in the treatment of pancreatic cancer as anadjunct to treatment with antiandrogen, or as monotherapy for theirantiandrogenic properties, offering the advantage over traditionalantiandrogens of being bone-sparing. Additionally, compounds of thisinvention can increase the number of blood cells, such as red bloodcells and platelets, and can be useful for the treatment ofhematopoietic disorders, such as aplastic anemia. Thus, consideringtheir tissue selective androgen receptor agonism listed above, thecompounds of this invention are ideal for hormone replacement therapy inhypogonadic (androgen deficient) men.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are useful as androgenreceptor agonists, in particular, as selective androgen receptoragonists. Compounds of the present invention are described by structuralformula I:

a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

-   X is hydrogen, or halogen;-   R¹ is hydrogen, CF₃, carbonyl C₁₋₃ alkyl, C₁₋₄ alkoxy, halogen, C₁₋₃    alkyl, (C₀₋₆ alkyl)₂amino C₀₋₆alkyl, and hydroxymethyl, wherein said    alkyl, and alkoxy are optionally substituted with one to seven    fluorine atoms;    -   represents a group chosen from:    -   a 5- or 6-membered monocyclic aromatic ring system having 0, 1,        2, 3 or 4 heteroatoms selected from the group consisting of N,        O, and S, and    -   a 9- to 14-membered polycyclic ring system, wherein one or more        of the rings is aromatic, and wherein the polycyclic ring system        has 0, 1, 2, 3 or 4 heteroatoms selected from the group        consisting of N, O, and S;-   R² and R³ are each independently chosen from    -   hydrogen,    -   halogen,    -   C₁₋₈ alkyl,    -   amino C₀₋₆alkyl,    -   C₁₋₆ alkylamino C₀₋₆alkyl,    -   (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   C₁₋₆ alkoxy C₀₋₆alkyl,    -   hydroxycarbonyl C₀₋₆alkyl,    -   C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   hydroxycarbonyl C₁₋₆ alkyloxy,    -   hydroxy C₀₋₆alkyl,    -   cyano,    -   perfluoroC₁₋₄alkyl,    -   perfluoroC₁₋₄alkoxy,    -   C₀₋₆ alkylcarbonyl,    -   C₁₋₆ alkylcarbonyloxy,    -   C₁₋₆ alkylcarbonylamino,    -   C₁₋₄ alkylsulfonylamino,    -   C₁₋₆alkoxycarbonylamino,    -   C₁₋₆alkylaminocarbonylamino,    -   (C₁₋₆alkyl)₂ aminocarbonylamino, and    -   (C₁₋₆alkyl)₂ aminocarbonyloxy,        and wherein-   R² and R³ together with the carbon atom to which they are attached    can optionally form a spiro-C₃₋₆ cycloalkyl group, or an oxo group,    and-   R² and R³ are each independently optionally substituted with one or    more R⁸,-   R⁴, R⁵, R⁶, and R⁷ are each independently chosen from:    -   hydrogen,    -   halogen,    -   (carbonyl)₀₋₁C₁₋₁₀ alkyl,    -   (carbonyl)₀₋₁₄C₂₋₁₀alkenyl,    -   (carbonyl)₀₋₁C₂₋₁₀ alkynyl,    -   (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁₀,    -   (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,    -   C₁₋₄acylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ akylamino C₀₋₁₀ alkylaminocarbonyl,    -   di-C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,    -   arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonylamino,    -   (C₁₋₁₀ alkyl)₂aminocarbonylamino,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonylamino,    -   C₀₋₁₀ alkyl aminocarbonylamino,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonylamino,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl C₀₋₁₀ alkyl,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀alkyl,    -   C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   aryl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl,    -   C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkyl carbonylamino(C₀₋₁₀ alkyl),    -   C₀₋₁₀ alkoxy carbonylamino(C₀₋₁₀ alkyl),    -   carboxy C₀₋₁₀ alkylamino,    -   carboxy C₀₋₁₀ alkyl,    -   carboxy aryl,    -   carboxy C₃₋₈ cycloalkyl,    -   carboxy C₃₋₈ heterocyclyl,    -   C₁₋₁₀alkoxy,    -   C₁₋₁₀alkyloxy C₀₋₁₀alkyl,    -   C₁₋₁₀ alkylcarbonyloxy,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy,    -   aryl C₀₋₁₀ alkylcarbonyloxy,    -   C₁₋₁₀ alkylcarbonyloxy amino,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy amino,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy amino,    -   aryl C₀₋₁₀ alkylcarbonyloxy amino,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy,    -   (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl) 12aminocarbonyloxy,    -   (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy,    -   hydroxy C₀₋₁₀alkyl,    -   hydroxycarbonylC₀₋₁₀alkoxy,    -   hydroxycarbonylC₀₋₁₀alkyloxy,    -   C₁₋₁₀ alkylthio,    -   C₁₋₁₀ alkylsulfinyl,    -   aryl C₀₋₁₀ alkylsulfinyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylsulfinyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alklsulfinyl,    -   C₁₋₁₀ alkylsulfonyl,    -   aryl C₀₋₁₀ alkylsulfonyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylsulfonyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfonyl,    -   C₁₋₁₀ alkylsulfonylamino,    -   aryl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,    -   cyano,    -   nitro,    -   perfluoroC₁₋₆alkyl, and    -   perfluoroC₁₋₆alkoxy,-   wherein R⁴, R⁵, R⁶, and R⁷ are each independently optionally    substituted with one or more R⁸;-   R⁸ is chosen from:    -   hydrogen,    -   halogen,    -   (carbonyl)₀₋₁C₁₋₁₀ alkyl,    -   (carbonyl)₀₋₁C₂₋₁₀ alkenyl,    -   (carbonyl)₀₋₁C₂₋₁₀ alkynyl,    -   (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl,    -   (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl,    -   C₁₋₄acylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   di-C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,    -   arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl,    -   C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,    -   C₁₋₁₀alkyloxy C₀₋₁₀alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   hydroxycarbonylC₀₋₁₀alkoxy,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy,    -   hydroxy C₀₋₁₀alkyl,    -   C₁₋₁₀ alkylsulfonyl,    -   C₁₋₁₀ alkylsulfonylamino,    -   aryl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,    -   cyano,    -   nitro,    -   perfluoroC₁₋₆alkyl, and    -   perfluoroC₁₋₆alkoxy,        wherein, R⁸ is optionally substituted with one or more groups        selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN,        O(C—O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,        —O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and        provided that when        is pyridinyl and R² is methyl then R³ is other than hydrogen.

In one embodiment of the invention,

is chosen from phenyl, naphthinyl, benzimidazolyl, benzofuranyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzodihydrofuranyl,1,3-benzodioxilyl, 2,3-dihydro-1,4-benzodioxinyl, quinoxalinyl,quinolizinyl, quinazolinyl, indazolyl, quinolyl, isoquinolyl, furanyl,thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, oxidopyridyl,isothiazolyl, isoindolyl, pyrazolyl, pyrrolyl, 1,6-dihydropyridinyl,pyridinyl, pyrimidinyl, pyrazinyl, pyrrolinyl, pyrazolinyl,thiadiazolyl, oxadiazolyl, tetrazolyl, and triazolyl.

In one variant of this embodiemnt,

is chosen from phenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,quinoxalinyl, oxidopyridyl, quinolizinyl, quinazolinyl, quinolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, 1,6-dihydropyridinyl,pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl, and thiadiazolyl, forexample, phenyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl, andthiazolyl such as for example, pyridinyl and pyrimidinyl.

In another embodiment,

is chosen from phenyl, pyrazinyl, pyridinyl, tetrazolyl, and thiazolyl.

In yet another embodiment, the compounds of the present invention areselected from structural formula I:

a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:

-   X is hydrogen, or halogen;-   R¹ is hydrogen, CF₃, halogen, C₁₋₃ alkyl, (C₀₋₆ alkyl)₂amino    C₀₋₆alkyl, and hydroxymethyl, wherein said alkyl, and alkoxy are    optionally substituted with one to seven fluorine atoms;    -   represents a group chosen from: phenyl, naphthinyl,        benzimidazolyl, benzofuranyl, benzothiophenyl, benzoxazolyl,        benzothiazolyl, benzodihydrofuranyl, quinoxalinyl, quinolizinyl,        quinazolinyl, 1,3-benzodioxilyl, 2,3-dihydro-1,4-benzodioxinyl,        indolyl, indazolyl, quinolyl, isoquinolyl, furanyl, thienyl,        imidazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl,        isoindolyl, oxidopyridyl, pyrazolyl, pyrrolyl,        1,6-dihydropyridinyl, pyridinyl, pyrimidinyl, pyrazinyl,        pyrrolinyl, pyrazolinyl, thiadiazolyl, oxadiazolyl, tetrazolyl,        and triazolyl;-   R², and R³ are each independently chosen from:    -   hydrogen, halogen,    -   C₁₋₈ alkyl,    -   amino C₀₋₆alkyl,    -   C₁₋₆ alkylamino C₀₋₆alkyl,    -   (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   (C₀₋₆alkyl)amino,    -   (C₀₋₆alkyl) carbonylamino,    -   C₁₋₆ alkoxy C₀₋₆alkyl,    -   hydroxycarbonyl C₀₋₆alkyl,    -   C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   hydroxycarbonyl C₁₋₆ alkyloxy,    -   hydroxy C₀₋₆alkyl,    -   cyano,    -   perfluoroC₁₋₄alkyl, and    -   perfluoroC₁₋₄alkoxy,        wherein-   R² and R³ together with the carbon atom to which they are attached    can optionally form a spiro-C₃₋₆ cycloalkyl group, or an oxo group,-   R² and R³ are each independently optionally substituted with one or    more R⁸;-   R⁴, R⁵, R⁶, and R⁷ are each independently chosen from:    -   hydrogen,    -   halogen,    -   (carbonyl)₀₋₁C₁₋₁₀ alkyl,    -   (carbonyl)₀₋₁C₂₋₁₀alkenyl,    -   (carbonyl)₀₋₁C₂₋₁₀ alkynyl,    -   (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁₀,    -   (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,    -   C₁₋₄acylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkylaminocarbonyl,    -   di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,    -   arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonylamino,    -   (C₁₋₁₀ alkyl)₂aminocarbonylamino,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonylamino,    -   C₀₋₁₀ alkyl aminocarbonylamino,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonylamino,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl C₀₋₁₀ alkyl,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl,    -   C₀₋₁₀alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   aryl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl,    -   C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkyl carbonylamino(C₀₋₁₀ alkyl),    -   C₀₋₁₀ alkoxy carbonylamino(C₀₋₁₀ alkyl),    -   carboxy C₀₋₁₀ alkylamino,    -   carboxy C₀₋₁₀ alkyl,    -   carboxy aryl,    -   carboxy C₃₋₈ cycloalkyl,    -   carboxy C₃₋₈ heterocyclyl,    -   C₁₋₁₀ alkoxy,    -   C₁₋₁₀alkyloxy C₀₋₁₀ alkyl,    -   C₁₋₁₀ alkylcarbonyloxy,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy,    -   aryl C₀₋₁₀ alkylcarbonyloxy,    -   C₁₋₁₀ alkylcarbonyloxy amino,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy amino,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy amino,    -   aryl C₀₋₁₀ alkylcarbonyloxy amino,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy,    -   (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy,    -   (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy,    -   hydroxy C₀₋₁₀alkyl,    -   hydroxycarbonylC₀₋₁₀alkoxy,    -   hydroxycarbonylC₀₋₁₀alkyloxy,    -   C₁₋₁₀ alkylthio,    -   C₁₋₁₀ alkylsulfinyl,    -   aryl C₀₋₁₀ alkylsulfinyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylsulfinyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfinyl,    -   C₁₋₁₀ alkylsulfonyl,    -   aryl C₀₋₁₀ alkylsulfonyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀alkylsulfonyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfonyl,    -   C₁₋₁₀ alkylsulfonylamino,    -   aryl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,    -   cyano,    -   nitro,    -   perfluoroC₁₋₆alkyl, and    -   perfluoroC₁₋₆alkoxy,        wherein R⁴, R⁵, R⁶, and R⁷ are each independently optionally        substituted with one or more R⁸;        R⁸ is chosen from:    -   hydrogen,    -   halogen,    -   (carbonyl)₀₋₁C₁₋₁₀ alkyl,    -   (carbonyl)₀₋₁C₂₋₁₀alkenyl,    -   (carbonyl)₀₋₁C₂₋₁₀ alkynyl,    -   (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl,    -   (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl,    -   C₁₋₄acylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,    -   arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl,    -   C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,    -   C₁₋₁₀alkyloxy C₀₋₁₀alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   hydroxycarbonylC₀₋₁₀alkoxy,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy,    -   hydroxy C₀₋₁₀alkyl,    -   C₁₋₁₀ alkylsulfonyl,    -   C₁₋₁₀ alkylsulfonylamino,    -   aryl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,    -   cyano,    -   nitro,    -   perfluoroC₁₋₆alkyl, and    -   perfluoroC₁₋₆alkoxy;        wherein, R⁸ is optionally substituted with one or more groups        selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN,        O(C—O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,        —O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and        provided that when        is pyridinyl and R² is methyl then R³ is other than hydrogen.

In another embodiment, X is halogen. In yet another embodiment, X ishydrogen.

In one embodiment, R¹ is selected from hydrogen, CF₃, halogen, C₁₋₃alkyl, (C₀₋₆ alkyl)₂amino C₀₋₆alkyl, and hydroxymethyl, wherein saidalkyl, and alkoxy are optionally substituted with one to seven fluorineatoms. In another embodiment, R¹ is chosen from hydrogen, CF₃, halogen,(C₀₋₆ alkyl)₂amino Cop alkyl, and C₁₋₃ alkyl. In a further embodiment,R¹ is chosen from hydrogen, and methyl.

In one embodiment, the compounds of the invention are chosen fromcompounds of formula I

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

-   X is hydrogen or halogen;-   R¹ is hydrogen, CF₃, halogen, C₁₋₃ alkyl, (C₀₋₆ alkyl)₂amino    C₀₋₆alkyl, and hydroxymethyl, wherein said alkyl, and alkoxy are    optionally substituted with one to seven fluorine atoms;    -   represents a group chosen from: phenyl, pyridinyl, and        pyrimidinyl;-   R² and R³ are each independently chosen from:    -   hydrogen,    -   halogen,    -   C₁₋₈ alkyl,    -   (C₀₋₆alkyl)amino,    -   (C₀₋₆alkyl) carbonylamino,    -   amino C₀₋₆alkyl,    -   C₁₋₆ alkylamino C₀₋₆alkyl,    -   (C₁₋₆ alkyl)₂amino C₀₋₆alkyl,    -   C₁₋₆ alkoxy C₀₋₆alkyl,    -   C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,    -   hydroxy C₀₋₆alkyl,    -   cyano,    -   perfluoroC₁₋₄alkyl, and    -   perfluoroC₁₋₄alkoxy,        wherein-   R² and R³ together with the carbon atom to which they are attached    can optionally form a spiro-C₃₋₆cycloalkyl group, or an oxo group,-   R² and R³ are each independently optionally substituted with one or    more R⁸;-   R⁴ is chosen from:    -   hydrogen,    -   (carbonyl)₀₋₁C₁₋₁₀ alkyl,    -   (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyl)₀₋₁,    -   (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   carboxy C₀₋₁₀alkyl,    -   carboxy aryl,    -   carboxy C₃₋₈ cycloalkyl,    -   carboxy C₃₋₈ heterocyclyl,    -   C₁₋₁₀alkyloxy C₀₋₁₀alkyl,    -   hydroxy C₀₋₁₀alkyl, and    -   perfluoroC₁₋₆alkyl,-   R⁴ is optionally substituted with one or more R⁸;-   R⁵, R⁶, and R⁷ are each independently chosen from:    -   hydrogen,    -   halogen,    -   (carbonyl)₀₋₁C₁₋₁₀ alkyl,    -   (carbonyl)₀₋₁C₂₋₁₀ alkenyl,    -   (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,    -   (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,    -   C₁₋₄acylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkylaminocarbonyl,    -   di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,    -   arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   (C₃₋₈ heterocyclyl C₀₋₁ alkyl₁₋₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonylamino,    -   (C₁₋₁₀ alkyl)₂aminocarbonylamino,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonylamino,    -   C₀₋₁₀ alkyl aminocarbonylamino,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonylamino,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl C₀₋₁₀ alkyl,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   aryl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl,    -   (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl,    -   C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkyl carbonylamino(C₀₋₁₀ alkyl),    -   C₀₋₁₀ alkoxy carbonylamino(C₀₋₁₀ alkyl),    -   carboxy C₀₋₁₀ alkylamino,    -   carboxy C₀₋₁₀ alkyl,    -   carboxy aryl,    -   carboxy C₃₋₈ cycloalkyl,    -   carboxy C₃₋₈ heterocyclyl,    -   C₁₋₁₀ alkoxy,    -   C₁₋₁₀alkyloxy C₀₋₁₀alkyl,    -   C₁₋₁₀ alkylcarbonyloxy,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy,    -   aryl C₀₋₁₀ alkylcarbonyloxy,    -   C₁₋₁₀ alkylcarbonyloxy amino,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy amino,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy amino,    -   aryl C₀₋₁₀ alkylcarbonyloxy amino,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy,    -   (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy,    -   (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy,    -   hydroxy C₀₋₁₀alkyl,    -   hydroxycarbonylC₀₋₁₀alkoxy,    -   hydroxycarbonylC₀₋₁₀alkyloxy,    -   C₁₋₁₀ alkylthio,    -   C₁₋₁₀ alkylsulfonyl,    -   aryl C₀₋₁₀ alkylsulfonyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylsulfonyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfonyl,    -   C₁₋₁₀ alkylsulfonylamino,    -   aryl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,    -   cyano,    -   nitro,    -   perfluoroC₁₋₆alkyl, and    -   perfluoroC₁₋₆alkoxy,-   wherein R⁵, R⁶, and R⁷ are each independently optionally substituted    with one or more R⁸;-   R⁸ is chosen from:    -   hydrogen,    -   halogen,    -   (carbonyl)₀₋₁C₁₋₁₀ alkyl,    -   (carbonyl)₀₋₁C₂₋₁₀ alkenyl,    -   (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkyl,    -   (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl,    -   C₁₋₄acylamino C₀₋₁₀ alkyl,    -   C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,    -   arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,    -   C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   C₃₋₈ heterocyclyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyl,    -   C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl,    -   C₁₋₁₀alkyloxy C₀₋₁₀alkyl,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   hydroxycarbonylC₀₋₁₀alkoxy,    -   (C₁₋₁₀ alkyl)₂aminocarbonyloxy,    -   hydroxy C₀₋₁₀alkyl,    -   C₁₋₁₀ alkylsulfonyl,    -   C₁₋₁₀ alkylsulfonylamino,    -   aryl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino,    -   C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,    -   cyano,    -   nitro,    -   perfluoroC₁₋₆alkyl, and    -   perfluoroC₁₋₆alkoxy, and        wherein R⁸ is optionally substituted with one or more groups        selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN,        O(C—O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,        —O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and        provided that when        is pyridinyl and R² is methyl then R³ is other than hydrogen.

Illustrative but nonlimiting examples of compounds of the presentinvention are the following:

-   N-[6-(trifluoromethyl)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(phenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-benzoxazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(quinoxalin-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyrazin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(nicotinamid-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methyl-1,3-benzothiazol-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyridin-2-yl)-4-methyl-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-(6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloropyridin-2-yl)-4-methyl-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methyl-1,2,4-thiadiazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-(trifluoromethyl)pyridin-2-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-nitro-1H-imidazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-ethyl-6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methoxy-6-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(5-bromo-6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(1H-benzimidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-pyrazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,6-dimethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1-oxidopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-ethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-6-aminopyridin-3-yl)methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(acetylamino)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(methyl    5-pyridin-2-ylcarbamate)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(pyridin-5-yl)-2,2-dimethylpropanamid-2-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(formylamino)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-imidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-cyanopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylisoxazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-chloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-tert-butylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-dimethoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-6-chloropyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-trifluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-difluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[3-(trifluoromethyl)phenyl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(trifluoromethyl)phenyl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(trifluoromethoxy)phenyl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-6-methylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(2-carboxamidyl)pyridin-5-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminopyrimidin-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-aminopyrimidin-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3,5-dichloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetanide;-   N-(3-methoxypyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-aminopyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(3-trifluoromethoxy)pyridin-4-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-ethylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methylquinolin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4-methylcarboxyl-phenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminopyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-5-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-3-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4-trifluoromethylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17>acetamide;-   N-(2-amino-5-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-5-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methyl-4-aminopyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-amino-5-trifluoromethylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-amino-4,6-dimethyl-5-chloropyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4,6-dimethylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-amino-4-methylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methylpyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-3-methoxycarbonylphenyl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-carboxamidophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-carboxamidophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-6-methylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-diaminopyrid-3-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(2-amino-5-methoxycarbonyl-pyrid-3-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(2-amino-5-methylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(4,6-dimethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(tetrazol-5-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,2-isothiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,2-thiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methyl-pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-trifluoromethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17>acetamide;-   N-[(6-trifluoromethyl)-pyrid-3-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-thiazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,3-thiazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-indazol-6-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(imidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(2,6-dimethyl)-1,3-pyrimid-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrazin-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-4-methyl-1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-benzimidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(3-carboxamido)-pyridin-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-3-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-4-methylpyrid-2-yl)-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(6-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-dimethylisoxazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-carboxyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyanopyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(mopholin-4-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(piperizin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(pyrollidin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(diamin-1-ylethylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(histaminylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(2-ethylamino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(1-hydroxymethyl)-propylaminocarbonyl]pyrid-2-yl-3-oxo-4-aza-5α-androst-1-en-17>acetamide;-   N-(5-[(2-methoxyethyl)-aminocarbonyl]pyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[2-(piperizinyl)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[3-morphilino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[2-morphilino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-[(3-methylamino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17>acetamide;-   N-[5-methoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(ethoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(isopropoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-cyano-4,6-dimethyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-bromo-6-methyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[methylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4    aza-5α-androst-1-en-17β-acetamide;-   N-{5-[N-2-methoxyethyl)-N-methyl-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-[N-(dimethylaminoethyl)-N-methyl-aminocarbonyl]pyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(ethoxycarbonyl)-4-methyl-pyrimid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(6-methyl)pyrid-3-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(carboxyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(carboxamido)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(N,N-dimethylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(N,N-dimethylamino)ethylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(N-methylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-carboxamido)-1H-imidazol-4-yl]-3-oxo-4-aza-5═-androst-1-en-17β-acetamide;-   N-[2    ethoxycarbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-[2-(carboxamido)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[2-(carboxyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[2-N-methylamino    carbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17>acetamide;-   N-[2-N,N-dimethylamino    carbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(hydroxylaminocarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-1H-tetrazol-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-aminopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-2,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(1H-pyrazol-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(pyrimidin-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(pyrimidin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-pyrazin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-2-furyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-bromopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-bromopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-3,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(pyrimidin-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[(aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[(N-methyl-aminocarbonyl)amino]pyrid-2-yl}-3-oxo-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[(N,N-dimethyl-aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{-[({[2-dimethylamino)ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[({[2-(N-piperidinyl)ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[({[2-morpholin-4-ethyl]amino}carbonyl)amino}pyrid-2-yl)-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[diethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{4-methyl-5-[dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[carboxamido]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(pyrizin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(phenylsulfonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(sulfonamido]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-sulfopyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[N-(diaminomethylene)-carbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-trifluoromethyl)pyridin-3-yl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-6-methylpyridin-3-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17>acetamide;-   N-[6-trifluoromethyl)pyridin-3-yl]-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-en-17β-acetamide;-   N-pyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-4-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-6-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17-acetamide;-   N-(5-chloropyridin-2-yl)-20-fluoro-4-methyl-3-α-4-aza-5α-androst-1-en-17β-acetamide;-   N-6-fluoropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methoxypyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-6-chloropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-2-yl)-20-fluoromethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-cyanopyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17-acetamide;-   N-(5-trifluromethylpyridin-2-yl)-20-fluoromethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyridin-2-yl)-20-fluoromethyl-3-oxaza-5α-androst-1-en-17β-acetamide;-   N-(1,3-thiazol-2-yl)-20-fluoro-4-methyl-3-oxo-1-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrimid-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyrizin-2-yl-20-fluoro    methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-chloropyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-dichloropyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyanopyridin-2-yl)-20-fluoromethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-benzoxazol-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylisoxazol-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(imidazol-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrazol-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(6-carboxamidopyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-methyl-N-3-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-3-yl)-20-hydroxymethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-4-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminopyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17    acetamide;-   N-[5-methylpyridin-2-yl]-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminomethoxycarbonyl-phenyl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-4-yl)-4-ethyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(3-carboxamidopyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrizin-4-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-2-yl)ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-thyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-dimethyl-1,3-thiazol-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-dimethyl-1,3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-carboxamidophenyl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridinyl)-20-aminomethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-20-hydroxymethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

In one embodiment, the compounds of the present invention are selectedfrom:

-   N-(phenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3,5-difluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-4-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[3-trifluoromethyl)phenyl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17>acetamide;-   N-(2-amino-4-methylcarboxyl-phenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-5-fluorophenyl)-4-methyl-3-oxo    4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-3-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-5-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-5-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

In one non-limiting embodiment, the compounds of the invention areselected from:

-   N-4-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-4-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-3-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methoxyphenyl-1)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3,5-difluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;    and    pharmaceutically acceptable salts and stereoisomers thereof.

In another embodiment the compounds of the present invention areselected from:

-   N-[6-(trifluoromethyl)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-5-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-dimethyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-trifluoromethyl)-1,3,4-thiadiazol-2-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-benzoxazol-2-yl)methyl-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-(quinoxalin-6-yl)-4-methyl-3-oxo    aza-5α-androst-1-en-17β-acetamide;-   N-(pyrazin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(nicotinamid-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-2-methyl-1,3-benzothiazol-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloropyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methyl-1,2,4-thiadiazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-[5-(trifluoromethyl)pyridin-2-yl]methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-nitro-1H-imidazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-ethyl-6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methoxy-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-bromo-6-methylpyridin-2-yl)₄    methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-benzimidazol-2-yl)-1-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-pyrazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,6    ethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1-oxidopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-ethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(pyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(acetylamino)pyridin-3-yl]4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(methyl    5-pyridin-2-ylcarbamate)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(pyridin-5-yl)-2,2-dimethylpropanamid-2-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(formylamino)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-(6-methoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-imidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-cyanopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylisoxazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-chloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-tert-butylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-dimethoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-chloropyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-[(2-carboxamidyl)pyridin-5-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminopyrimidin-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-aminopyrimidin-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3,5-dichloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-(3-methoxypyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-aminopyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(3-trifluoromethoxy)pyridin-4-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-ethylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-oxo-1,6-dihydropyridin-3-yl)-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methylquinolinyl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(2-aminopyrid-3-yl)+methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(4,6-dimethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(tetrazol-5-yl)-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(pyridin-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,2-isothiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,2-thiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methyl-pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-trifluoromethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(6-trifluoromethyl)-pyrid-3-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-thiazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,3-thiazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-indazolyl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-imidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(2,6-dimethyl)-1,3-pyrimid-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrazin-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(benzimidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(3-carboxamido)-pyridin-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   NS-fluoropyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-dimethylisoxazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-carboxyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyanopyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-171-acetamide;-   N-[5-mopholin-4-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(piperizin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(pyrollidin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-[5-(diamin-1-ylethylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(histaminylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(2-ethylamino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(1-hydroxymethyl)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(2-methoxyethyl)-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[2-(piperizinyl)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[3-morphilino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[2-(morphilino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(3-dimethylamino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-[5-(methoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-ethoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-isopropoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-cyano-4-dimethyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-bromo-6-methyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-[6-(fluoromethyl)pyridin-3-yl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-3-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(trifluoromethyl)pyridin-3-yl]-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloropyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-fluoropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methoxypyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-chloropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-6-methylpyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-cyanopyridin-3-yl)-20-fluoromethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-20-hydroxy    methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

In yet another embodiment, the compounds of the present invention areselected from:

-   N-[6-(trifluoromethyl)pyridin-3-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloropyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17-acetamide;-   N-(4-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(trifluoromethyl)pyridin-2-yl]4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;    and-   N-(3-ethyl-6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methoxy-6-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-bromo-6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,6-dimethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-oxidopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-ethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-acetylamino)pyridin-3-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(methyl    5-pyridin-2-ylcarbamate)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(pyridin-5-yl)-2,2-dimethylpropanamid-2-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(formylamino)pyridin-3-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-cyanopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-chloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-dimethoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-chloropyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(2-carboxamidyl)pyridin-5-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-(2-aminopyrimidin-5-yl)+methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-aminopyrimidin-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3,5-dichloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methoxypyridin-4-yl)-4-methyl-3-oxo    4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-aminopyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(3-trifluoromethoxy)pyridin-4-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-ethylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminopyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-nicotinamid-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(4,6-dimethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methyl-pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-trifluoromethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(6-trifluoromethyl)-pyrid-3-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(2,6-dimethyl)-1,3-pyrimid-4-yl]-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(3-carboxamido)-pyridin-6-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-5-fluoropyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-carboxyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyanopyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-mopholin-4-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-piperizin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-pyrollidin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(diamin-1-ylethylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(histaminylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-175-acetamide;-   N-{5-[(2-ethylamino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo    4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(1-hydroxymethyl)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(2-methoxyethyl)-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-[2-piperizinyl)-ethylaminocarbonyl]pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[3-morphilino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[2-(morphilino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(3-dimethylamino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-[5-(methoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(ethoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(isopropoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-cyano-4,6-dimethyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(5-bromo-6-methyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-trifluoromethyl)pyridin-3-yl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-3-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(trifluoromethyl)pyridin-3-yl]-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloropyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-fluoropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methoxypyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-chloropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17-acetamide;-   N-(3-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-cyanopyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

In yet another varient of the invention, the compounds are selectedfrom:

-   N-(6-(trifluoromethyl)pyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-cyanopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(nicotinamid-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-3-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methoxy-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17>acetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

In one embodiment of the invention, the compounds are selected from:

-   N-(5-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-dimethyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-trifluoromethyl)-1,3,4-thiadiazol-2-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-benzoxazol-2-yl)-4-methyl-3-oxo-aza-5α-androst-1-en-17β-acetamide;-   N-quinoxalin-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrazin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methyl-1,3-benzothiazol-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methyl-1,2,4-thiadiazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-nitro-1H-imidazol-5-yl)-4-methyl-3-oxo    4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-benzimidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-pyrazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-imidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylisoxazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-tert-butylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(tetrazol-5-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,2-isothiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,2-thiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-1,3-thiazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methyl-1,3-thiazol-2-yl)-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-indazol-6-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(imidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrazin-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methylquinolin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(benzimidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-dimethylisoxazol-2-yl)-3-oxo    4-aza-5α-androst-1-en-17βacetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

In yet another non-limiting embodiment the compounds of the inventionare selected from:

-   N-(5-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrazin-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-imidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1H-benzimidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

In yet another embodiment, the compounds of the present invention arechosen from:

-   N-(6-methyl-4-aminopyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-amino-5-trifluoromethylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-amino-4,6-dimethyl-5-chloropyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4,6-dimethylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-amino-4-methylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-methylpyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-3-methoxycarbonylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-carboxamidophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-carboxamidophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-methylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-2,6-diaminopyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-5-methoxycarbonyl-pyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-5-methylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[methylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[N-2-methoxyethyl)-N-methyl-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[N-dimethylaminoethyl)-N-methyl-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-ethoxycarbonyl)-4-methyl-pyrimid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-ethoxycarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-[(6-methyl)pyrid-3-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(carboxyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-carboxamido)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(N,N-dimethylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[(N,N-dimethylamino)ethylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[4-(N-methylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-carboxamido)-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[2-ethoxycarbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[2-carboxamido)-1-methyl-1H-imidazol-4-yl])-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[2-carboxyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[2-(N-methylamino    carbonyl)-1-methyl-1H-imidazol-1-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[2-N,N-dimethylamino    carbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(hydroxylaminocarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(1H-tetrazol-5-yl)pyrid-2-yl]-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-aminopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(1H-pyrazol-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-[5-(pyrimidin-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(pyrimidin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(pyrazin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-(2-furyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-3,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-bromopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-bromopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17βacetamide;-   N-[6-(pyrimidin-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-[(aminocarbonyl)amino]pyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[(N-methyl-aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[(N,N-dimethyl-aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[({[2-(dimethylamino)ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[([2-(N-piperidinyl)ethyl]amino}carbonyl)amino]pyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-171    acetamide;-   N-{6-[({[2-morpholin-4-ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4-methyl-5-[dimethylaminocarbonyl]pyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{6-[carboxamido]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[6-(pyrizin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[(phenylsulfonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-{5-[(sulfonamido]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-sulfopyrid-2-yl}-3-oxa-4-aza-5α-androst-1-en-17β-acetamide;-   N-{5-[N-diaminomethylene)-carbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-(5-trifluromethylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza--androst-1-en-17β-acetamide;-   N-(1,3-thiazol-2-yl)-20-fluoromethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(1,3-pyrimid-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyrizin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-chloropyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2,6-dichloropyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-(2-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyanopyridin-2-yl)-20-fluoromethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-chloro-1,3-benzoxazol-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-methylisoxazol-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-imidazol-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-pyrazol-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-carboxamidopyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-methyl-N-(3-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-4-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-aminopyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-[5-methylpyridin-2-yl]4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(2-amino-4-methoxycarbonyl-phenyl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-2-yl) thyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-3-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-pyridin-4-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17-acetamide;-   N-(5-carboxamidopyridin-2-yl)-4-ethyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(pyrizin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-fluoropyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-aminopyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-(4,5-ethyl-1,3-thiazol-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-4-ethyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(4,5-ethyl-1,3-thiazol-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;-   N-(5-methylpyridin-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(3-carboxamidophenyl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;-   N-(pyridin-4-yl)-20-amino-4-methyl-3-oxo-4-aza-5-androst-1-en-17β-acetamide;-   N-(6-methylpyridin-2-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;    and pharmaceutically acceptable salts and stereoisomers thereof.

The compounds of the present invention can have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochem-istry of Carbon Compounds, John Wiley & Sons, NewYork, 1994, pages 1119-1190), and occur as racemates, racemic mixtures,and as individual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein can exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof. The term Z represents the remainder of the 4-azasteroidderivatives of the present invention.

The term “alkyl” shall mean straight or branched chain alkanes of one toten total carbon atoms, or any number within this range (i.e., methyl,ethyl, 1-propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.). The term“C₀ alkyl” (as in “C₀₋₈ alkylaryl”) shall refer to the absence of analkyl group.

The term “alkenyl” shall mean straight or branched chain alkenes of twoto ten total carbon atoms, or any number within this range.

The term “alkynyl” refers to a hydrocarbon radical straight, branched orcyclic, containing from 2 to 10 carbon atoms and at least one carbon tocarbon triple bond. Up to three carbon-carbon triple bonds can bepresent Thus, “C₂-C₆ alkynyl” means an alkynyl radical having from 2 to6 carbon atoms. Alkynyl groups include ethynyl, propynyl, butynyl,3-methylbutynyl and so on. The straight, branched or cyclic portion ofthe alkynyl group can contain triple bonds and can be substituted if asubstituted alkynyl group is indicated.

“Cycloalkyl” as used herein is intended to include non-aromatic cyclichydrocarbon groups, having the specified number of carbon atoms, whichmay or may not be bridged or structurally constrained. Examples of suchcycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, cycloheptyl,tetrahydro-naphthalene, methylenecylohexyl, and the like. As usedherein, examples of “C₃-C₁₀ cycloalkyl” can include, but are not limitedto:

“Alkoxy” represents either a cyclic or non-cyclic alkyl group ofindicated number of carbon atoms attached through an oxygen bridge.“Alkoxy” therefore encompasses the definitions of alkyl and cycloalkylabove.

“Perfluoroalkyl” represents alkyl chains of up to 10 carbon atoms havingexhaustive substitution of their corresponding hydrogens with fluorineatoms.

As used herein, “aryl” is intended to mean any stable monocyclic orbicyclic carbon ring of up to 7 atoms in each ring, wherein at least onering is aromatic. Examples of such aryl elements include, but are notlimited to, phenyl, naphthyl, tetrahydro-naphthyl, indanyl, or biphenyl.In cases where the aryl substituent is bicyclic and one ring isnon-aromatic, it is understood that attachment is via the aromatic ring.

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms chosen from O, N and S.Heteroaryl groups within the scope of this definition include but arenot limited to: acridinyl, carbazolyl, cinnolinyl, quinoxalinyl,pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl,benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl,pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl,tetrahydroquinoline. As with the definition of heterocycle below,“heteroaryl” is also understood to include the N-oxide derivative of anynitrogen-containing heteroaryl.

In cases where the heteroaryl substituent is bicyclic and one ring isnon-aromatic or contains no heteroatoms, it is understood thatattachment is via the aromatic ring or via the heteroatom containingring, respectively.

Whenever the term “alkyl” or “aryl” or either of their prefix rootsappears in a name of a substituent (e.g., aryl C₀₋₈ alkyl), it shall beinterpreted as including those limitations given above for “alkyl” and“aryl.” Designated numbers of carbon atoms (e.g., C₀₋₈) shall referindependently to the number of carbon atoms in an alkyl or cyclic alkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo. The term“heterocycle” or “heterocyclyl” as used herein is intended to mean a 5-to 10-membered aromatic or nonaromatic heterocycle containing from 1 to4 heteroatoms selected from the group consisting of O, N and S, andincludes bicyclic groups. “Heterocyclyl” therefore includes the abovementioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl,thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl,dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

The terms “arylalkyl” and “alkylaryl” include an alkyl portion wherealkyl is as defined above and include an aryl portion where aryl is asdefined above. Examples of arylalkyl include, but are not limited to,benzyl, phenylethyl, phenylpropyl, naphthylmethyl, and naphthylethyl.Examples of alkylaryl include, but are not limited to, toluene,ethylbenzene, propylbenzene, methylpyridine, ethylpyridine,propylpyridine and butylpyridine.

The term “oxy” means an oxygen (O) atom. The term “thio” means a sulfur(S) atom. The term “oxo” means “═O”. The term “carbonyl” means “C═O.”

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

When any variable (e.g., R⁵, R⁶, etc.) occurs more than one time in anysubstituent or in formula I, its definition in each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², R³,etc., are to be chosen in conformity with well-known principles ofchemical structure connectivity.

Lines drawn into the ring systems from substituents indicate that theindicated bond can be attached to any of the substitutable ring atoms.If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups can be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases one embodiment will have fromzero to three substituents.

In one embodiment of the invention, R¹ is chosen from hydrogen, (C₀₋₆alkyl)₂amino C₀₋₆alkyl, and C₁₋₃ alkyl, wherein said alkyl is optionallysubstituted with one to seven fluorine atoms. In a variant of thisembodiment, R¹ is chosen from hydrogen, CF₃, and C₁₋₃ alkyl.

In one embodiment, R² and R³ are each independently chosen from:hydrogen, halogen, hydroxyl, and C₁₋₈ alkyl. In a further embodiment, R²and R³ are each hydrogen.

In another embodiment, R² and R³ together with the carbon atom to whichthey are attached form a spiro-C₃₋₆ cycloalkyl group, such as forexample, cyclopropyl, or an oxo group.

In yet another embodiment of the invention, R⁵, R⁶, and R⁷ are eachindependently chosen from: hydrogen, halogen, (carbonyl)₀₋₁C₀₋₁₀ alkyl,C₃₋₈ cycloalkylC₀₋₁₀alkyl(carbonyl)₀₋₁, C₀₋₁₀ alkylaminoC₀₋₁₀alkyl,C₀₋₁₀alkylamino C₀₋₁₀ alkylaminocarbonyl, C₀₋₁₀ alkylcarbonylamino(C₀₋₁₀alkyl), C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, C₃₋₈heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, C₁₋₁₀ alkoxy(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkoxy carbonylamino(C₀₋₁₀alkyl), C₁₋₁₀alkoxy, C₁₋₁₀alkyloxy C₀₋₁₀alkyl, C₁₋₁₀ alkylthio, cyano, perfluoroC₁₋₆alkyl, and perfluoroC₁₋₆alkoxy. In another embodiment, the alkyl,alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl groups of R⁵, R⁶,and R⁷ are each independently, optionally substituted with at least onesubstituent chosen from: hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN,O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂.

In another embodiment, R⁴ is chosen from: hydrogen, (carbonyl)₀₋₁C₁₋₁₀alkyl, (carbonyl)₀₋₁C₂₋₁₀ alkenyl, (carbonyl)₀₋₁C₂₋₁₀ alkynyl,(carbonyl)₀₋₁aryl C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,C₁₋₄acylamino C₀₋₁₀ alkyl, C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₀₋₁₀alkylamino C₀₋₁₀ alkylaminocarbonyl, di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl, (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylamino C₀₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,(C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₂aminocarbonyl C₀₋₁₀ alkyl, (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀alkyl, C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀alkyl aminocarbonyl C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkylaminocarbonyl C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,(C₀₋₁₀ alkyl)₂ aminocarbonyl, (aryl C₁₋₁₀ alkyl)₁₋₂ aminocarbonyl, C₁₋₁₀alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkyl carbonylamino (C₀₋₁₀alkyl), C₀₋₁₀ alkoxy carbonylamino(C₀₋₁₀ alkyl), carboxy C₀₋₁₀ alkyl,carboxy C₃₋₈ cycloalkyl, C₁₋₁₀alkyloxy C₀₋₁₀alkyl, hydroxy C₀₋₁₀alkyl,C₁₋₁₀ alkylthio, C₀₋₁₀ alkylsulfinyl, aryl C₀₋₁₀ alkylsulfinyl, C₃₋₈heterocyclyl C₀₋₁₀ alkylsulfinyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfinyl,C₁₋₁₀ alkylsulfonyl, aryl C₀₋₁₀ alkylsulfonyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylsulfonyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfonyl, andperfluoroC₁₋₆alkyl.

In yet another embodiment of the invention, R⁴ is chosen from hydrogen,halogen, (carbonyl)₀₋₁C₁₋₁₀ alkyl, C₀₋₁₀ alkylamino C₀₋₁₀ alkyl,perfluoroC₁₋₆alkyl, and perfluoroC₁₋₆alkoxy. In a variant of thisembodiment, R⁴ is chosen from: hydrogen, halogen, C₁₋₁₀ alkyl, andperfluoroC₁₋₆alkyl. In yet another embodiment of the invention, R⁴ ishydrogen.

Compounds of the present invention have been found to betissue-selective modulators of the androgen receptor (SARMs). In oneaspect, compounds of the present invention can be useful to activate thefunction of the androgen receptor in a mammal, and in particular toactivate the function of the androgen receptor in bone and/or muscletissue and block or inhibit (“antagonize”) the function of the androgenreceptor in the prostate of a male individual or in the uterus of afemale individual.

A further aspect of the present invention is the use of compounds offormula I to attenuate or block the function of the androgen receptor inthe prostate of a male individual or in the uterus of a femaleindividual induced by AR agonists, but not in hair-growing skin or vocalcords, and activate the function of the androgen receptor in bone and/ormuscle tissue, but not in organs which control blood lipid levels (e.g.liver).

The compounds of the present invention can be used to treat conditionswhich are caused by androgen deficiency, which can be ameliorated byandrogen replacement, or which can be increased by androgen replacement,including, but not limited to osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, bone fracture,such as for example, vertebral and non-vertebral fractures, bone damagefollowing bone reconstructive surgery, sarcopenia, frailty, aging skin,male hypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia and otherhematopoietic disorders, arthritic condition and joint repair,HIV-wasting, Alzheimer's disease, prostate cancer, cancer cachexia,muscular dystrophies, Alzheimer's disease, cognitive impairment,decreased libido, premature ovarian failure, and autoimmune disease,alone or in combination with other active agents. Treatment is effectedby administration of a therapeutically effective amount of a compound ofstructural formula I to a mammal in need of such treatment. In addition,these compounds are useful as ingredients in pharmaceutical compositionsalone or in combination with other active agents.

In one embodiment, the compounds of the present invention can be used totreat conditions in a male individual which are caused by androgendeficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, periodontal disease, HIV-wasting,prostate cancer, cancer cachexia, obesity, arthritic conditions,anemias, such as for example, aplastic anemia, muscular dystrophies, andAlzheimer's disease, alone or in combination with other active agents.Treatment is effected by administration of a therapeutically effectiveamount of a compound of structural formula I to a male individual inneed of such treatment.

“Arthritic condition” or “arthritic conditions” refers to a diseasewherein inflammatory lesions are confined to the joints or anyinflammatory conditions of the joints, most notably osteoarthritis andrheumatoid arthritis (Academic Press Dictionary of Science Technology;Academic Press; 1st edition, Jan. 15, 1992). The compounds of Formula Iare also useful, alone or in combination, to treat or prevent arthriticconditions, such as Behcet's disease; bursitis and tendinitis; CPPDdeposition disease; carpal tunnel syndrome; Ehlers-Danlos syndrome;fibromyalgia; gout; infectious arthritis; inflammatory bowel disease;juvenile arthritis; lupus erythematosus; lyme disease; marfan syndrome;myositis; osteoarthritis; osteogenesis imperfecta; osteonecrosis;polyarteritis; polymyalgia rheumatica; psoriatic arthritis; Raynaud'sphenomenon; reflex sympathetic dystrophy syndrome; Reiter's syndrome;rheumatoid arthritis; scleroderma; and Sjogren's syndrome. An embodimentof the invention encompasses the treatment or prevention of an arthriticcondition which comprises administering a therapeutically effectiveamount of a Compound of Formula I. A subembodiment is the treatment orprevention of osteoarthritis, which comprises administering atherapeutically effective amount of a Compound of Formula I. See: CutoloM, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A. Ann. N.Y.Acad. Sci. 2002 June; 966:131-42; Cutolo, M. Rheum Dis Clin North Am2000 November; 26(4):881-95; Bijlsma J W, Van den Brink H R. Am J ReprodImmunol 1992 October-December; 28(3-4):231-4; Jansson L, Holmdahl R.;Arthritis Rheum 2001 September; 44(9):2168-75; and Purdie D W. Br MedBull 2000; 56(3):809-23. Also, see Merck Manual, 17th edition, pp.449-451.

When used in combination to treat arthritic conditions, the Compounds ofFormula I can be used with any of the drugs disclosed herein as usefulfor combination therapy, or can be used with drugs known to treat orprevent arthritic conditions, such as corticosteroids, cytoxic drugs (orother disease modifying or remission inducing drugs), gold treatment,methotrexate, NSAIDs, and COX-2 inhibitors.

In another embodiment, the compounds of the present invention can beused to treat conditions in a female individual which are caused byandrogen deficiency or which can be ameliorated by androgen replacement,including, but not limited to, osteoporosis, osteopenia,glucocorticoid-induced osteoporosis, postmenopausal symptoms,periodontal disease, HIV-wasting, cancer cachexia, obesity, anemias,such as for example, aplastic anemia, muscular dystrophies, Alzheimer'sdisease, premature ovarian failure, and autoimmune disease, alone or incombination with other active agents. Treatment is effected byadministration of a therapeutically effective amount of a compound ofstructural formula I to a female individual in need of such treatment.

The compounds of formula I are also useful in the enhancement of muscletone in mammals, such as for example, humans.

The compounds of structural formula I can also be employed as adjunctsto traditional androgen depletion therapy in the treatment of prostatecancer to restore bone, minimize bone loss, and maintain bone mineraldensity. In this manner, they can be employed together with traditionalandrogen deprivation therapy, including GnRH agonists/antagonists, suchas those disclosed in P. Limonta, et al., “LHRH analogues as anticanceragents: pituitary and extrapituitary sites of action,” Exp. Opin.Invest. Drugs. 10: 709-720 (2001); H. J. Stricker, “Luteinizinghormone-releasing hormone antagonists,” Urology 58 (Suppl. 2A): 24-27(2001); R. P. Millar, et al., “Progress towards the development ofnon-peptide orally-active GnRH antagonists,” British Medical Bulletin,56: 761-772 (2000); and A. V. Schally et al., “Rational use of agonistsand antagonists of LH-RH in the treatment of hormone-sensitive neoplasmsand gynecologic conditions,” Advanced Drug Delivery Reviews, 28: 157-169(1997). The compounds of structural formula I can be used in combinationwith antiandrogens, such as flutamide, 2-hydroxyflutamide (the activemetabolite of flutamide), nilutamide, and bicalutamide (Casodex™) in thetreatment of prostate cancer.

Further, the compounds of the present invention can also be employed inthe treatment of pancreatic cancer, either for their androgen antagonistproperties or as an adjunct to an antiandrogen, such as flutamide,2-hydroxyflutamide (the active metabolite of flutamide), nilutamide, andbicalutamide (Casodex™).

The term “treating cancer” or “treatment of cancer” refers toadministration to a mammal afflicted with a cancerous condition andrefers to an effect that alleviates the cancerous condition by killingthe cancerous cells, but also to an effect that results in theinhibition of growth and/or metastasis of the cancer.

Compounds of structural formula I can minimize the negative effects onlipid metabolism. Therefore, considering their tissue selective androgenagonistic properties, the compounds of this invention exhibit advantagesover existing approaches for hormone replacement therapy in hypogonadic(androgen deficient) male individuals.

Additionally, compounds of the present invention can increase the numberof blood cells, such as red blood cells and platelets, and can be usedfor treatment of hematopoietic disorders, such as aplastic anemia.

Representative compounds of the present invention typically displaysubmicromolar binding affinity for the androgen receptor. Compounds ofthis invention are therefore useful in treating mammals suffering fromdisorders related to androgen receptor function. Therapeuticallyeffective amounts of the compound, including the pharmaceuticallyacceptable salts thereof, are administered to the mammal, to treatdisorders related to androgen receptor function, or which can beimproved by the addition of additional androgen, such as for example,osteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, hematopoietic disorders,such as for example, aplastic anemia, pancreatic cancer, Alzheimer'sdisease, inflammatory arthritis, and joint repair.

The compounds of the present invention can be admisistered in theirenantiomerically pure form. Racemic mixtures can be separated into theirindividual enantiomers by any of a number of conventional methods. Theseinclude chiral chromatography, derivatization with a chiral auxiliaryfollowed by separation by chromatography or crystallization, andfractional crystallization of diastereomeric salts.

As used herein, a compound of the present invention which functions asan “agonist” of the androgen receptor can bind to the androgen receptorand initiate a physiological or a pharmacological responsecharacteristic of that receptor. The term “tissue-selective androgenreceptor modulator” refers to an androgen receptor ligand that mimicsthe action of a natural ligand in some tissues but not in others. A“partial agonist” is an agonist which is unable to induce maximalactivation of the receptor population, regardless of the amount ofcompound applied. A “full agonist” induces full activation of theandrogen receptor population at a given concentration. A compound of thepresent invention which functions as an “antagonist” of the androgenreceptor can bind to the androgen receptor and block or inhibit theandrogen-associated responses normally induced by a natural androgenreceptor ligand.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Non-limitingrepresentive salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. In one variantof the invention, the salts are chosen from the ammonium, calcium,lithium, magnesium, potassium, and sodium salts. Non-limiting examplesof salts derived from pharmaceutically acceptable organic non-toxicbases include salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, and basic ion exchange resins, such as arginine, betaine,caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts can beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Representative acids which can be employedinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic,phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonicacid, trifluoroacetic acid, and the like. In one variant, the acids areselected from citric, fumaric, hydrobromic, hydrochloric, maleic,phosphoric, sulfuric, and tartaric acids.

The preparation of the pharmaceutically acceptable salts described aboveand other typical pharmaceutically acceptable salts is more fullydescribed by Berg et al., “Pharmaceutical Salts,” J. Parm. Sci.,1977:66:1-19.

It would also be noted that the compounds of the present invention arepotentially internal salts or zwitterions, since under physiologicalconditions a deprotonated acidic moiety in the compound, such as acarboxyl group, may be anionic, and this electronic charge might then bebalanced off internally against the cationic charge of a protonated oralkylated basic moiety, such as a quaternary nitrogen atom.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts.

By “pharmaceutically acceptable” it is meant that the carrier, diluentor excipient must be compatible with the other ingredients of theformulation and not be deleterious to the recipient thereof.

The terms “administration of a compound” and “administering a compound”should be understood to mean providing a compound of the invention or aprodrug of a compound of the invention to the individual in need oftreatment.

By the term “modulating a function mediated by the androgen receptor ina tissue selective manner” it is meant modulating a function mediated bythe androgen receptor selectively (or discriminately) in anabolic (boneand/or muscular) tissue (bone and muscular) in the absence of suchmodulation at androgenic (reproductive) tissue, such as the prostate,testis, seminal vesicles, ovary, uterus, and other sex accessorytissues. In one embodiment, the function of the androgen receptor inanabolic tissue is activated whereas the function of the androgenreceptor in androgenic tissue is blocked or suppressed.

The administration of a compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to thepatient in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well-known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician in charge of the case, but depends on factorssuch as the exact disease to be treated, the severity of the disease andother diseases or conditions from which the patient suffers, the chosenroute of administration, other drugs and treatments which the patientcan concomitantly require, and other factors in the physician'sjudgment.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention can alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

Generally, the daily dosage of a compound of structural formula I can bevaried over a wide range from 0.01 to 1000 mg per adult human per day.For example, dosages range from 0.1 to 200 mg/day. For oraladministration, the compositions can be provided in the form of tabletscontaining 0.01 to 1000 mg, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2.5,3.0, 5.0, 6.0, 10.0, 15.0, 25.0, 50.0, 75, 100, 125, 150, 175, 180, 200,225, and 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the mammal to be treated.

The dose can be administered in a single daily dose or the total dailydosage can be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose can be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through an intravenous solution, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

Formulations of the tissue-selective androgen receptor modulatoremployed in the present method for medical use comprise a compound ofstructural formula I together with an acceptable carrier thereof andoptionally other therapeutically active ingredients. The carrier must bepharmaceutically acceptable in the sense of being compatible with theother ingredients of the formulation and not being deleterious to therecipient subject of the formulation.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of structural formula I together witha pharmaceutically acceptable carrier thereof.

The formulations include those suitable for intranasal, oral, rectal,intravaginal, topical or parenteral (including subcutaneous,intramuscular and intravenous administration). In one embodiment, theformulations are those suitable for oral administration.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compounds of the present inventionordinarily include about 0.005% to about 5% by weight of the activecompound in admixture with a pharmaceutically acceptable vehicle.Transdermal skin patches useful for administering the compounds of thepresent invention include those well known to those of ordinary skill inthat art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

The formulations can be presented in a unit dosage form and can beprepared by any of the methods known in the art of pharmacy. All methodsinclude the step of bringing the active compound in association with acarrier, which constitutes one or more ingredients. In general, theformulations are prepared by uniformly and intimately bringing theactive compound in association with a liquid carrier, a waxy solidcarrier or a finely divided solid carrier, and then, if needed, shapingthe product into the desired dosage form.

Formulations of the present invention suitable for oral administrationcan be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension or solution in an aqueousliquid or non-aqueous liquid, e.g., a syrup, an elixir, or an emulsion.

A tablet can be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets can be prepared bycompressing in a suitable machine the active compound in a free flowingform, e.g., a powder or granules, optionally mixed with accessoryingredients, e.g., binders, lubricants, inert diluents, disintegratingagents or coloring agents. Molded tablets can be made by molding in asuitable machine a mixture of the active compound, preferably inpowdered form, with a suitable carrier. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethyl-cellulose,polyethylene glycol, waxes and the like. Non-limiting representativelubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

Oral liquid forms, such as syrups or suspensions in suitably flavoredsuspending or dispersing agents such as the synthetic and natural gums,for example, tragacanth, acacia, methyl cellulose and the like, can bemade by adding the active compound to the solution or suspension.Additional dispersing agents which can be employed include glycerin andthe like.

Formulations for vaginal or rectal administration can be presented as asuppository with a conventional carrier, i.e., a base that is nontoxicand nonirritating to mucous membranes, compatible with a compound ofstructural formula I, and is stable in storage and does not bind orinterfere with the release of the compound of structural formula I.Suitable bases include: cocoa butter (theobroma oil), polyethyleneglycols (such as carbowax and polyglycols), glycol-surfactantcombinations, polyoxyl 40 stearate, polyoxyethylene sorbitan fatty acidesters (such as Tween, Myrj, and Arlacel), glycerinated gelatin, andhydrogenated vegetable oils. When glycerinated gelatin suppositories areused, a preservative such as methylparaben or propylparaben can beemployed.

Topical preparations containing the active drug component can be admixedwith a variety of carrier materials well known in the art, such as,e.g., alcohols, aloe vera gel, allantoin, glycerine, vitamin A and Eolis, mineral oil, PPG2 myristyl propionate, and the like, to form,e.g., alcoholic solutions, topical cleansers, cleansing creams, skingels, skin lotions, and shampoos in cream or gel formulations.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention can also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention can alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinyl-pyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamidephenol, or polyethylene-oxide polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention can be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross-linked or amphipathic block copolymers of hydrogels.

Formulations suitable for parenteral administration include formulationsthat comprise a sterile aqueous preparation of the active compound whichcan be isotonic with the blood of the recipient. Such formulationssuitably comprise a solution or suspension of a compound that isisotonic with the blood of the recipient subject. Such formulations cancontain distilled water, 5% dextrose in distilled water or saline andthe active compound. Often it is useful to employ a pharmaceutically andpharmacologically acceptable acid addition salt of the active compoundthat has appropriate solubility for the solvents employed. Usefulformulations also comprise concentrated solutions or solids comprisingthe active compound which on dilution with an appropriate solvent give asolution suitable for parenteral administration.

The compounds of the present invention can be coupled to a class ofbiodegradable polymers useful in achieving controlled release of a drug,for example, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans,polycyanoacrylates, and cross-linked or amphipathic block copolymers ofhydrogels.

The pharmaceutical composition and method of the present invention canfurther comprise other therapeutically active compounds usually appliedin the treatment of the above mentioned conditions, includingosteoporosis, periodontal disease, bone fracture, bone damage followingbone reconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, post-menopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, hematopoietic disorders, such asfor example, aplastic anemia, pancreatic cancer, Alzheimer's disease,inflammatory arthritis, and joint repair.

For the treatment and prevention of osteoporosis, the compounds of thepresent invention can be administered in combination with abone-strengthening agent selected from antiresorptive agents,osteoanabolic agents, and other agents beneficial for the skeletonthrough mechanisms which are not precisely defined, such as calciumsupplements, flavonoids, and vitamin D analogs. The conditions ofperiodontal disease, bone fracture, and bone damage following bonereconstructive surgery can also benefit from these combined treatments.For example, the compounds of the instant invention can be effectivelyadministered in combination with effective amounts of other agents suchas estrogens, bisphosphonates, SERMs, cathepsin K inhibitors, αvβ3integrin receptor antagonists, vacuolar ATPase inhibitors, thepolypeptide osteoprotegerin, antagonists of VEGF, thiazolidinediones,calcitonin, protein kinase inhibitors, parathyroid hormone (PTH) andanalogs, calcium receptor antagonists, growth hormone secretagogues,growth hormone releasing hormone, insulin-like growth factor, bonemorphogenetic protein (BMP), inhibitors of BMP antagonism, prostaglandinderivatives, fibroblast growth factors, vitamin D and derivativesthereof, vitamin K and derivatives thereof, soy isoflavones, calciumsalts, and fluoride salts. The conditions of periodontal disease, bonefracture, and bone damage following bone reconstructive surgery can alsobenefit from these combined treatments.

In one embodiment of the present invention, a compound of the instantinvention can be effectively administered in combination with aneffective amount of at least one bone-strengthening agent chosen fromestrogen, and estrogen derivatives, alone or in combination withprogestin or progestin derivatives; bisphosphonates; antiestrogens orselective estrogen receptor modulators; αvβ3 integrin receptorantagonists; cathepsin K inhibitors; osteoclast vacuolar ATPaseinhibitors; calcitonin; and osteoprotegerin.

In the treatment of osteoporosis, the activity of the compounds of thepresent invention are distinct from that of the anti-resorptive agents:estrogens, bisphosphonates, SERMs, calcitonin, cathepsin K inhibitors,vacuolar ATPase inhibitors, agents interfering with theRANK/RANKL/Osteoprotegerin pathway, p38 inhibitors or any otherinhibitors of osteoclast generation or osteoclast activation. Ratherthan inhibiting bone resorption, the compounds of structural formula Iaid in the stimulation of bone formation, acting, for example, oncortical bone, which is responsible for a significant part of bonestrength. The thickening of cortical bone substantially contributes to areduction in fracture risk, especially fractures of the hip. Thecombination of the tissue-selective androgen receptor modulators ofstructural formula I with anti-resorptive agents such as for exampleestrogen, bisphosphonates, antiestrogens, SERMs, calcitonin, αvβ3integrin receptor antagonists, HMG-CoA reductase inhibitors, vacuolarATPase inhibitors, and cathepsin K inhibitors is particularly useful dueto the complementory effect of the bone anabolic and antiresorptiveactions.

Bone antiresportive agents are those agents which are known in the artto inhibit the resorption of bone and include, for example, estrogen andestrogen derivatives which include steroidal compounds having estrogenicactivity such as, for example, 17β-estradiol, estrone, conjugatedestrogen (PREMARIN®), equine estrogen, 17β-ethynyl estradiol, and thelike. The estrogen or estrogen derivative can be employed alone or incombination with a progestin or progestin derivative. Nonlimitingexamples of progestin derivatives are norethindrone andmedroxy-progesterone acetate.

Bisphosphonates are also bone anti-resorptive agents. Non-limitingexamples of bisphosphonate compounds which can also be employed incombination with a compound of structural formula I of the presentinvention include:

-   (a) alendronate (also known as alendronic acid,    4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid, alendronate    sodium, alendronate monosodium trihydrate or    4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid monosodium    trihydrate. Alendronate is described in U.S. Pat. No. 4,922,007, to    Kieczykowski et al., issued May 1, 1990; U.S. Pat. No. 5,019,651, to    Kieczykowski, issued May 28, 1991; U.S. Pat. No. 5,510,517, to Dauer    et al., issued Apr. 23, 1996; U.S. Pat. No. 5,648,491, to Dauer et    al., issued Jul. 15, 1997, all of which are incorporated by    reference herein in their entirety;-   (b) [(cycloheptylamino)-methylene]-bis-phosphonate (incadronate),    which is described in U.S. Pat. No. 4,970,335, to Isomura et al.,    issued Nov. 13, 1990, which is incorporated by reference herein in    its entirety;-   (c) (dichloromethylene)-bis-phosphonic acid (clodronic acid) and the    disodium salt (clodronate), which are described in Belgium Patent    672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of which are    incorporated by reference herein in their entirety;-   (d) [1-hydroxy-3-(1-pyrrolidinyl)-propylidene]-bis-phosphonate    (EB-1053);-   (e) (1-hydroxyethylidene)-bis-phosphonate (etidronate);-   (f) [1-hydroxy-3-(methylpentylamino)propylidene]-bis-phosphonate    (ibandronate), which is described in U.S. Pat. No. 4,927,814, issued    May 22, 1990, which is incorporated by reference herein in its    entirety;-   (g) (6-amino-1-hydroxyhexylidene)-bis-phosphonate (neridronate);-   (h) [3-(dimethylamino)-1-hydroxypropylidene]-bis-phosphonate    (olpadronate);-   (i) (3-amino-1-hydroxypropylidene)-bis-phosphonate (pamidronate);-   (j) [2-(2-pyridinyl)ethylidene]-bis-phosphonate (piridronate), which    is described in U.S. Pat. No. 4,761,406, which is incorporated by    reference in its entirety;-   (k) [1-hydroxy-2-(3-pyridinyl)-ethylidene]-bis-phosphonate    (risedronate);-   (l) {[(4-chlorophenyl)thio]methylene}-bis-phosphonate (tiludronate),    which is described in U.S. Pat. No. 4,876,248, to Breliere et al.,    Oct. 24, 1989, which is incorporated by reference herein in its    entirety;-   (m) [1-hydroxy-2-(1H-imidazol-1-yl)ethylidene]-bis-phosphonate    (zoledronate); and-   (n)    [1-hydroxy-2-imidazopyridin-(1,2-a)-3-ylethylidene]-bis-phosphonate    (minodronate).

In one embodiment of the methods and compositions of the presentinvention, the bisphosphonate is selected from the group chosen fromalendronate, clodronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, pamidronate, piridronate,risedronate, tiludronate, zoledronate, pharmaceutically acceptable saltsof these bisphosphonates, and mixtures thereof. In one variant, thebisphosphonate is selected from alendronate, risedronate, zoledronate,ibandronate, tiludronate, and clodronate. In a subclass of this class,the bisphosphonate is alendronate, pharmaceutically acceptable salts andhydrates thereof, and mixtures thereof. A particular pharmaceuticallyacceptable salt of alendronate is alendronate monosodium.Pharmaceutically acceptable hydrates of alendronate monosodium includethe monohydrate and the trihydrate. A particular pharmaceuticallyacceptable salt of risedronate is risedronate monosodium.Pharmaceutically acceptable hydrates of risedronate monosodium includethe hemi-pentahydrate.

Still further, antiestrogenic compounds such as raloxifene (see, e.g.,U.S. Pat. No. 5,393,763), clomiphene, zuclomiphene, enclomiphene,nafoxidene, CI-680, CI-628, CN-55,945-27, Mer-25, U-11,555A, U-100A, andsalts thereof, and the like (see, e.g., U.S. Pat. Nos. 4,729,999 and4,894,373) can be employed in combination with a compound of structuralformula I in the methods and compositions of the present invention.These agents are also known as SERMs, or selective estrogen receptormodulators, agents known in the art to prevent bone loss by inhibitingbone resorption via pathways believed to be similar to those ofestrogens.

SERMs can be used in combination with the compounds of the Formula I tobeneficially treat bone disorders including osteoporosis. Such agentsinclude, for example, tamoxifen, raloxifene, lasofoxifene, toremifene,azorxifene, EM-800, EM-652, TSE 424, clomiphene, droloxifene, idoxifene,and levormeloxifene [Goldstein, et al., “A pharmacological review ofselective estrogen receptor modulators,” Human Reproduction Update, 6:212-224 (2000), and Lufkin, et al., “The role of selective estrogenreceptor modulators in the prevention and treatment of osteoporosis,”Rheumatic Disease Clinics of North America, 27: 163-185 (2001)]. SERMsare also discussed in “Targeting the Estrogen Receptor with SERMs,” Ann.Rep. Med. Chef 36: 149-158 (2001).

αvβ3 Integrin receptor antagonists suppress bone resorption and can beemployed in combination with the tissue selective androgen receptormodulators of structural formula I for the treatment of bone disordersincluding osteoporosis. Peptidyl as well as peptidomimetic antagonistsof the αvβ3 integrin receptor have been described both in the scientificand patent literature. For example, reference is made to W. J. Hoekstraand B. L. Poulter, Curr. Med. Chem 5: 195-204 (1998) and referencescited therein; WO 95/32710; WO 95/37655; WO 97/01540; WO 97/37655; WO98/08840; WO 98/18460; WO 98/18461; WO 98/25892; WO 98/31359; WO98/30542; WO 99/15506; WO 99/15507; WO 00/03973; EP 853084; EP 854140;EP 854145; U.S. Pat. Nos. 5,204,350; 5,217,994; 5,639,754; 5,741,796;5,780,426; 5,929,120; 5,952,341; 6,017,925; and 6,048,861.

Evidence of the ability of αvβ3 integrin receptor antagonists to preventbone resorption in vitro and in vivo has been presented (see V. W.Engleman et al., “A Peptidomimetic Antagonist of the αvβ3 IntegrinInhibits Bone Resorption In Vitro and Prevents Osteoporosis In Vivo,” J.Clin. Invest 99: 2284-2292 (1997); S. B. Rodan et al., “A High AffinityNon-Peptide αvβ3 Ligand Inhibits Osteoclast Activity In Vitro and InVivo,” J. Bone Miner. Res. 11: S289 (1996); J. F. Gourvest et al.,“Prevention of OVX-Induced Bone Loss With a Non-peptidic Ligand of theαvβ3 Vitronectin Receptor,” Bone 23: S612 (1998); M. W. Lark et al., “AnOrally Active Vitronectin Receptor αvβ3 Antagonist Prevents BoneResorption In Vitro and In Vivo in the Ovariectomized Rat,” Bone 23:S219 (1998)). Other αvβ3 antagonists are described in R. M. Keenan etal., “Discovery of Potent Nonpeptide Vitronectin Receptor (αvβ3)Antagonists,” J. Med. Cherm 40: 2289-2292 (1997); R. M. Keenan et al.,“Benzimidazole Derivatives As Arginine Mimetics in 1,4-BenzodiazepineNonpeptide Vitronectin Receptor (αvβ3) Antagonists,” Bioorg. Med. Chem.Lett. 8: 3165-3170 (1998); and R. M. Keenan et al., “Discovery of anImidazopyridine-Containing 1,4-Benzodiazepine Nonpeptide VitronectinReceptor (αvβ3) Antagonist With Efficacy in a Restenosis Model,” Bioorg.Med. Chem. Lett. 8: 3171-3176 (1998).

Still other benzazepine, benzodiazepine and benzocycloheptene αvβ3integrin receptor antagonists are described in the following patentpublications: WO 96/00574, WO 96/00730, WO 96/06087, WO 96/26190, WO97/24119, WO 97/24122, WO 97/24124, WO 98/14192, WO 98/15278, WO99/05107, WO 99/06049, WO 99/15170, WO 99/15178, WO 99/15506, and U.S.Pat. No. 6,159,964, and WO 97/34865. αvβ3 integrin receptor antagonistshaving dibenzocycloheptene, dibenzocycloheptane and dibenzoxazepinescaffolds have been described in WO 97/01540, WO 98/30542, WO 99/11626,WO 99/15508, WO 00/33838, U.S. Pat. Nos. 6,008,213, and 6,069,158.

Other osteoclast integrin receptor antagonists incorporating backboneconformational ring constraints have been described in the patentliterature. Published patent applications or issued patents disclosingantagonists having a phenyl constraint include WO 98/00395, WO 99/32457,WO 99/37621, WO 99/44994, WO 99/45927, WO 99/52872, WO 99/52879, WO99/52896, WO 00/06169, EP 0 820,988, EP 0 820,991, U.S. Pat. Nos.5,741,796; 5,773,644; 5,773,646; 5,843,906; 5,852,210; 5,929,120;5,952,381; 6,028,223; and 6,040,311. Published patent applications orissued patents disclosing antagonists having a monocyclic ringconstraint include WO 99/26945, WO 99/30709, WO 99/30713, WO 99/31099,WO 99/59992, WO 00/00486, WO 00/09503, EP 0 796,855, EP 0 928,790, EP 0928,793, U.S. Pat. Nos. 5,710,159; 5,723,480; 5,981,546; 6,017,926; and6,066,648. Published patent applications or issued patents disclosingantagonists having a bicyclic ring constraint include WO 98/23608, WO98/35949, WO 99/33798, EP 0 853,084, U.S. Pat. Nos. 5,760,028;5,919,792; and 5,925,655.

Reference is also made to the following reviews for additionalscientific and patent literature that concern alpha v integrinantagonists: M. E. Duggan, et al., “Ligands to the integrin receptorα_(v)β₃ , Exp. Opin. Ther. Patents, 10: 1367-1383 (2000); M. Gowen, etal., “Emerging therapies for osteoporosis,” Emerging Drugs 5: 143(2000); J. S. Kerr, et al., “Small molecule α_(v) integrin antagonists:novel anticancer agents,” Exp. Opin. Invest. Drugs, 9: 1271-1291 (2000);and W. H. Miller, et al., “Identification and in vivo efficacy ofsmall-molecule antagonists of integrin α_(v)β₃ (the vitronectinreceptor),” Drug Discovery Today, 5: 397-408 (2000).

Cathepsin K, formerly known as cathepsin O2, is a cysteine protease andis described in PCT International Application Publication No. WO96/13523, published May 9, 1996; U.S. Pat. No. 5,501,969, issued Mar. 3,1996; and U.S. Pat. No. 5,736,357, issued Apr. 7, 1998, all of which areincorporated by reference herein in their entirety. Cysteine proteases,specifically cathepsins, are linked to a number of disease conditions,such as tumor metastasis, inflammation, arthritis, and bone remodeling.At acidic pH's, cathepsins can degrade type-I collagen. Cathepsinprotease inhibitors can inhibit osteoclastic bone resorption byinhibiting the degradation of collagen fibers and are thus useful in thetreatment of bone resorption diseases, such as osteoporosis.Non-limiting examples of cathespin K inhibitors can be found in PCTInternational Publications assigned to Merck Frost Canada and AxixPharmaceuticals: WO 01/49288, published Jul. 7, 2001, and WO 01/77073,published Oct. 18, 2001.

Members of the class of HMG-CoA reductase inhibitors, known as the“statins,” have been found to trigger the growth of new bone, replacingbone mass lost as a result of osteoporosis (see The Wall Street Journal,Friday, Dec. 3, 1999, page B1). Therefore, the statins hold promise forthe treatment of bone resorption. Examples of HMG-CoA reductaseinhibitors include statins in their lactonized or dihydroxy open acidforms and pharmaceutically acceptable salts and esters thereof,including but not limited to lovastatin (see U.S. Pat. No. 4,342,767);simvastatin (see U.S. Pat. No. 4,444,784); dihydroxy open-acidsimvastatin, particularly the ammonium or calcium salts thereof;pravastatin, particularly the sodium salt thereof (see U.S. Pat. No.4,346,227); fluvastatin, particularly the sodium salt thereof (see U.S.Pat. No. 5,354,772); atorvastatin, particularly the calcium salt thereof(see U.S. Pat. No. 5,273,995); cerivastatin, particularly the sodiumsalt thereof (see U.S. Pat. No. 5,177,080), rosuvastatin, also known asZD-4522 (see U.S. Pat. No. 5,260,440) and pitavastatin, also referred toas NK-104, itavastatin, or nisvastatin (see PCT internationalapplication publication number WO 97/23200).

Osteoclast vacuolar ATPase inhibitors, also called proton pumpinhibitors, can also be employed together with the tissue selectiveandrogen receptor modulators of structural formula I. The proton ATPasewhich is found on the apical membrane of the osteoclast has beenreported to play a significant role in the bone resorption process.Therefore, this proton pump represents an attractive target for thedesign of inhibitors of bone resorption which are potentially useful forthe treatment and prevention of osteoporosis and related metabolicdiseases [see C. Farina et al., “Selective inhibitors of the osteoclastvacuolar proton ATPase as novel bone antiresorptive agents,” DDT, 4:163-172 (1999)].

The angiogenic factor VEGF has been shown to stimulate thebone-resorbing activity of isolated mature rabbit osteoclasts viabinding to its receptors on osteoclasts [see M. Nakagawa et al.,“Vascular endothelial growth factor (VEGF) directly enhancesosteoclastic bone resorption and survival of mature osteoclasts,” FEBSLetters, 473: 161-164 (2000)]. Therefore, the development of antagonistsof VEGF binding to osteoclast receptors, such as KDR/Flk-1 and Flt-1,can provide yet a further approach to the treatment or prevention ofbone resorption.

Activators of the peroxisome proliferator-activated receptor-γ (PPARγ),such as the thiazolidinediones (TZD's), inhibit osteoclast-like cellformation and bone resorption int vitro. Results reported by R. Okazakiet al. in Endocrinology 140: 5060-5065 (1999) point to a local mechanismon bone marrow cells as well as a systemic one on glucose metabolismNonlimiting examples of PPARγ, activators include the glitazones, suchas troglitazone, pioglitazone, rosiglitazone, and BRL 49653.

Calcitonin can also be employed together with the tissue selectiveandrogen receptor modulator of structural formula I. Calcitonin ispreferentially employed as salmon nasal spray (Azra et al., Calcitonin.1996. In: J. P. Bilezildan, et al., Ed., Principles of Bone Biology, SanDiego: Academic Press; and Silverman, “Calcitonin,” Rheumatic DiseaseClinics of North America, 27: 187-196, 2001)

Protein kinase inhibitors can also be employed together with the tissueselective androgen receptor modulators of structural formula I. Kinaseinhibitors include those disclosed in WO 01/17562 and are in oneembodiment selected from inhibitors of p38. Non-limiting examples of p38inhibitors useful in the present invention include SB 203580 [Badger etal., “Pharmacological profile of SB 203580, a selective inhibitor ofcytokine suppressive binding protein/p38 kinase, in animal models ofarthritis, bone resorption, endotoxin shock, and immune function,” J.Pharmacol. Exp. Ther., 279: 1453-1461 (1996)].

Osteoanabolic agents are those agents that are known to build bone byincreasing the production of the bone protein matrix. Such osteoanabolicagents include, for example, the various forms of parathyroid hormone(PTH) such as naturally occurring PTH (1-84), PTH (1-34), analogsthereof, native or with substitutions and particularly parathyroidhormone subcutaneous injection. PTH has been found to increase theactivity of osteoblasts, the cells that form bone, thereby promoting thesynthesis of new bone (Modern Drug Discovery, Vol. 3, No. 8, 2000). Aninjectable recombinant form of human PTH, Forteo (teriparatide), hasreceived regulatory approval in the U.S. for the treatment ofosteoporosis. Thus, PTH and fragments thereof, such as hPTH(1-34), canprove to be efficacious in the treatment of osteoporosis alone or incombination with other agents, such as the tissue selective androgenreceptor modulators of the present invention.

Also useful in combination with the SARMs of the present invention arecalcium receptor antagonists which induce the secretion of PTH asdescribed by Gowen et al., in “Antagonizing the parathyroid calciumreceptor stimulates parathyroid hormone secretion and bone formation inosteopenic rats,” J. Clin. Invest. 105: 1595-604 (2000).

Additional osteoanabolic agents include growth hormone secretagogues,growth hormone, growth hormone releasing hormone and the like can beemployed with the compounds according to structural formula I for thetreatment of osteoporosis. Representative growth hormone secretagoguesare disclosed in U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S.Pat. No. 4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241;U.S. Pat. No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No.5,317,017; U.S. Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat.No. 5,434,261; U.S. Pat. No. 5,438,136; U.S. Pat. No. 5,494,919; U.S.Pat. No. 5,494,920; U.S. Pat. No. 5,492,916; U.S. Pat. No. 5,536,716;EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT PatentPub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub.No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO95/34311; PCT Patent Pub. No. WO 96/02530; Science. 20 1640-1643 (Jun.11, 1993); Ann. Rep. Med. Chem., 28: 177-186 (1993); Bioorg. Med. Chem.Lett., 4: 2709-2714 (1994); and Proc. Natl. Acad. Sci. USA. 92:7001-7005 (1995).

Insulin-like growth factor (IGF) can also be employed together with thetissue selective androgen receptor modulators of structural formula I.Insulin-like growth factors can be selected from Insulin-like GrowthFactor I, alone or in combination with IGF binding protein 3 and IGF II[See Johannson and Rosen, “The IGFs as potential therapy for metabolicbone diseases,” 1996, In: Bilezikian, et al., Ed., Principles of BoneBiology, San Diego: Academic Press; and Ghiron et al., “Effects ofrecombinant insulin-like growth factor-I and growth hormone on boneturnover in elderly women,” J. Bone Miner. Res. 10: 1844-1852 (1995)].

Bone morphogenetic protein (BMP) can also be employed together with thetissue selective androgen receptor modulators of structural formula I.Bone morphogenetic protein includes BMP 2, 3, 5, 6, 7, as well asrelated molecules TGF beta and GDP F [Rosen et al., “Bone morphogeneticproteins,” 1996. In: J. P. Bilezikian, et al., Ed., Principles of BoneBiology, San Diego: Academic Press; and Wang E A, “Bone morphogeneticproteins (BMPs): therapeutic potential in healing bony defects,” TrendsBiotechnol., 11: 379-383 (1993)].

Inhibitors of BMP antagonism can also be employed together with thetissue selective androgen receptor modulators of structural formula I.In one embodiment, BMP antagonist inhibitors are chosen from inhibitorsof the BMP antagonists SOST, noggin, chordin, gremlin, and dan [Massagueand Chen, “Controlling TGF-beta signaling,” Genes Dev., 14: 627-644,2000; Aspenberg et al., “The bone morphogenetic proteins antagonistNoggin inhibits membranous ossification,” J. Bone Miner. Res. 16:497-500, 2001; Brunkow et al., “Bone dysplasia sclerosteosis resultsfrom loss of the SOST gene product, a novel cystine knot-containingprotein,” Am. J. Hum. Genet 68: 577-89 (2001)].

The tissue-selective androgen receptor modulators of the presentinvention can also be combined with the polypeptide osteoprotegerin forthe treatment of conditions associated with bone loss, such asosteoporosis. The osteoprotegerin can be selected from mammalianosteoprotegerin and human osteoprotegerin. The polypeptideosteoprotegerin, a member of the tumor necrosis factor receptorsuper-family, is useful to treat bone diseases characterized byincreased bone loss, such as osteoporosis. Reference is made to U.S.Pat. No. 6,288,032, which is incorporated by reference herein in itsentirety.

Prostaglandin derivatives can also be employed together with the tissueselective androgen receptor modulators of structural formula I.Non-limiting representatives of prostaglandin derivatives are selectedfrom agonists of prostaglandin receptors EP1, EP2, EP4, FP, IP andderivatives thereof [Pilbeam et al., “Prostaglandins and bonemetabolism,” 1996. In: Bilezikian, et al. Ed. Principles of BoneBiology, San Diego: Academic Press; Weinreb et al., “Expression of theprostaglandin E(2) (PGE(2)) receptor subtype EP(4) and its regulation byPGE(2) in osteoblastic cell lines and adult rat bone tissue,” Bone, 28:275-281 (2001)].

Fibroblast growth factors can also be employed together with the tissueselective androgen receptor modulators of structural formula I.Fibroblast growth factors include aFGF, bFGF and related peptides withFGF activity [Hurley Florkiewicz, “Fibroblast growth factor and vascularendothelial growth factor families,” 1996. In: J. P. Bilezikian, et al.,Ed. Principles of Bone Biology, San Diego: Academic Press].

In addition to bone resorption inhibitors and osteoanabolic agents,there are also other agents known to be beneficial for the skeletonthrough mechanisms which are not precisely defined. These agents canalso be favorably combined with the tissue selective androgen receptormodulators of structural formula I.

Vitamin D and vitamin D derivatives can also be employed together withthe tissue selective androgen receptor modulator of structural formulaI. Vitamin D and vitamin D derivatives include, for example, naturalvitamin D, 25-OH-vitamin D3, 1α,25(OH)₂ vitamin D3, 1α-OH-vitamin D3,1α-OH-vitamin D2, dihydrotachysterol, 26,27-F6-1α,25(OH)₂ vitamin D3,19-nor-1α,25(OH)₂ vitamin D3, 22-oxacalcitriol, calcipotriol,1α,25(OH)₂-16-ene-23-yne-vitamin D3 (Ro 23-7553), EB1089,20-epi-1α,25(OH)₂ vitamin D3, KH1060, ED71, 1α,24(S)—(OH)₂ vitamin D3,1α,24(R)—(OH)₂ vitamin D3 [See, Jones G., “Pharmacological mechanisms oftherapeutics: vitamin D and analogs,” 1996. In: J. P. Bilezikian, et al.Ed. Principles of Bone Biology, San Diego: Academic Press].

Vitamin K and vitamin K derivatives can also be employed together withthe tissue selective androgen receptor modulators of structural formulaI. Vitamin K and vitamin K derivatives include menatetrenone (vitaminK2) [see Shiraki et al., “Vitamin K2 (menatetrenone) effectivelyprevents fractures and sustains lumbar bone mineral density inosteoporosis,” J. Bone Miner. Res., 15: 515-521 (2000)].

Soy isoflavones, including ipriflavone, can be employed together withthe tissue selective androgen receptor modulators of structural formulaI.

Fluoride salts, including sodium fluoride (NaF) and monosodiumfluorophosphate (MFP), can also be employed together with the tissueselective androgen receptor modulators of structural formula I. Dietarycalcium supplements can also be employed together with the tissueselective androgen receptor modulators of structural formula I. Dietarycalcium supplements include calcium carbonate, calcium citrate, andnatural calcium salts (Heaney. Calciuim 1996. In: J. P. Bilezikian, etal., Ed., Principles of Bone Biology, San Diego: Academic Press).

Daily dosage ranges for bone resorption inhibitors, osteoanabolic agentsand other agents which can be used to benefit the skeleton when used incombination with a compound of structural formula I are those which areknown in the art. In such combinations, generally the daily dosage rangefor the tissue selective androgen receptor modulator of structuralformula I is 0.01 to 1000 mg per adult human per day, such as forexample, from 0.1 to 200 mg/day. However, adjustments to decrease thedose of each agent can be made due to the increased efficacy of thecombined agent.

In particular, when a bisphosphonate is employed, dosages of 2.5 to 100mg/day (measured as the free bisphosphonic acid) are appropriate fortreatment, such as for example ranging from 5 to 20 mg/day, or about 10mg/day. Prophylactically, doses of about 2.5 to about 10 mg/day andespecially about 5 mg/day should be employed. For reduction inside-effects, it can be desirable to administer the combination of acompound of structural formula I and the bisphosphonate once a week. Foronce weekly administration, doses of about 15 mg to 700 mg per week ofbisphosphonate and 0.07 to 7000 mg of a compound of structural formula Ican be employed, either separately, or in a combined dosage form Acompound of structural formula I can be favorably administered in acontrolled-release delivery device, particularly for once weeklyadministration.

For the treatment of atherosclerosis, hypercholesterolemia, andhyperlipidemia, the compounds of structural formula I can be effectivelyadministered in combination with one or more additional active agents.The additional active agent or agents can be chosen from lipid-alteringcompounds such as HMG-CoA reductase inhibitors, agents having otherpharmaceutical activities, and agents that have both lipid-alteringeffects and other pharmaceutical activities. Non-limiting examples ofHMG-CoA reductase inhibitors include statins in their lactonized ordihydroxy open acid forms and pharmaceutically acceptable salts andesters thereof, including but not limited to lovastatin (see U.S. Pat.No. 4,342,767); simvastatin (see U.S. Pat. No. 4,444,784); dihydroxyopen-acid simvastatin, particularly the ammonium or calcium saltsthereof; pravastatin, particularly the sodium salt thereof (see U.S.Pat. No. 4,346,227); fluvastatin, particularly the sodium salt thereof(see U.S. Pat. No. 5,354,772); atorvastatin, particularly the calciumsalt thereof (see U.S. Pat. No. 5,273,995); cerivastatin, particularlythe sodium salt thereof (see U.S. Pat. No. 5,177,080), and nisvastatin,also referred to as NK-104 (see PCT international applicationpublication number WO 97/23200).

Additional active agents which can be employed in combination with acompound of structural formula I include, but are not limited to,HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; cholesterol absorption inhibitors, such asSCH-58235, also known as ezetimibe and1-(4-fluorophenyl)-3(R)-[3(S)-4-fluorophenyl)-3-hydroxypropyl)]-4(S)-(4-hydroxyphenyl)-2-azetidinone,which is described in U.S. Pat. Nos. 5,767,115 and 5,846,966; bile acidsequestrants; LDL (low density lipoprotein) receptor inducers; plateletaggregation inhibitors, for example glycoprotein IIb/IIIa fibrinogenreceptor antagonists and aspirin; human peroxisome proliferatoractivated receptor gamma (PPARγ), agonists, including the compoundscommonly referred to as glitazones, for example troglitazone,pioglitazone and rosiglitazone and, including those compounds includedwithin the structural class known as thiazolidinediones as well as thosePPARγ, agonists outside the thiazolidinedione structural class; PPARαagonists, such as clofibrate, fenofibrate including micronizedfenofibrate, and gemfibrozil; PPAR dual α/γ agonists; vitamin B₆ (alsoknown as pyridoxine) and the pharmaceutically acceptable salts thereofsuch as the HCl salt; vitamin B₁₂ (also known as cyanocobalamin); folicacid or a pharmaceutically acceptable salt or ester thereof such as thesodium salt and the methylglucamine salt; anti-oxidant vitamins such asvitamin C and E and beta carotene; beta-blockers; angiotensin IIantagonists such as losartan; angiotensin converting enzyme inhibitors,such as enalapril and captopril; calcium channel blockers, such asnifedipine and diltiazem; endothelin antagonists; agents such as LXRligands that enhance ABC1 gene expression; bisphosphonate compounds,such as alendronate sodium; and cyclooxygenase-2 inhibitors, such asrofecoxib and celecoxib, as well as other agents known to be useful inthe treatment of these conditions.

Daily dosage ranges for HMG-CoA reductase inhibitors when used incombination with the compounds of structural formula I correspond tothose which are known in the art. Similarly, daily dosage ranges for theHMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalenesynthetase inhibitors (also known as squalene synthase inhibitors),acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors includingselective inhibitors of ACAT-1 or ACAT-2 as well as dual inhibitors ofACAT-1 and -2; microsomal triglyceride transfer protein (MTP)inhibitors; probucol; niacin; cholesterol absorption inhibitorsincluding ezetimibe; bile acid sequestrants; LDL (low densitylipoprotein) receptor inducers; platelet aggregation inhibitors,including glycoprotein IIb/IIIa fibrinogen receptor antagonists andaspirin; human peroxisome proliferator activated receptor gamma (PPARγ)agonists; PPARα agonists; PPAR dual α/γ agonists; vitamin B₆; vitaminB₁₂; folic acid; anti-oxidant vitamins; beta-blockers; angiotensin IIantagonists; angiotensin converting enzyme inhibitors; calcium channelblockers; endothelin antagonists; agents such as LXR ligands thatenhance ABC1 gene expression; bisphosphonate compounds; andcyclooxygenase-2 inhibitors also correspond to those which are known inthe art, although due to the combined action with the compounds ofstructural formula I the dosage can be somewhat lower when administeredin combination.

One embodiment of the invention is a method for affecting a boneturnover marker in a mammal comprising administering a therapeuticallyeffective amount of a compound according to formula I. Non-limitingexamples of bone turnover markers can be selected from urinaryC-telopeptide degradation products of type I collagen (CTX), urinaryN-telopeptide cross-links of type I collagen (NIX), osteocalcin (boneGla protein), dual energy x-ray absorptionmetry (DXA), bone specificalkaline phosphatase (BSAP), quantitative ultrasound (QUS), anddeoxypyridinoline (DPD) crosslinks.

In accordance with the method of the present invention, the individualcomponents of the combination can be administered separately atdifferent times during the course of therapy or concurrently in dividedor single combination forms. The instant invention is therefore to beunderstood as embracing all such regimes of simultaneous or alternatingtreatment and the term “administering” is to be interpreted accordingly.It will be understood that the scope of combinations of the compounds ofthis invention with other agents useful for treating diseases caused byandrogen deficiency or that can be ameliorated by addition of androgen.

Abbreviations Used in the Description of the Preparation of theCompounds of the Present Invention:

-   AcOH Acetic acid-   DHT Dihydrotestosterone-   DMAP 4-Dimethylaminopyridine-   DMEM Dulbecceo modified eagle media-   DMSO Dimethyl sulfoxide-   DMF N,N-Dimethylformamide-   EA Ethyl acetate-   EDC 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide HCl-   EDTA Ethylenediaminetetraacetic acid-   EtOH Ethanol-   Et₃N Triethylamine-   FCS Fetal calf serum-   HEPES (2-Hydroxyethyl)-1-piperazineethanesulfonic acid-   HOAt 1-hydroxy-7-azabenzotriazole-   HPLC High-performance liquid chromatography-   KHMDS Potassium bistrimethylsilylamide-   LCMS Liquid chromotography/mass spectroscopy-   LDA Lithium diisopropylamide-   LG Leaving group-   MeOH Methanol-   n-Bu4NI Tetra-n-butylammonium iodide-   PMBCL p-Methoxybenzyl chloride-   p-TosCl p-Toluenesulfonyl chloride-   Rt Room temperature-   TFA Trifluoroacetic acid-   TLC Thin-layer chromatography

The compounds of this invention may be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature or exemplified in theexperimental procedures. The illustrative schemes below, therefore, arenot limited by the compounds listed or by any particular substitutentsemployed for illustrative purposes. Substituent numbering as shown inthe schemes does not necessarily correlate to that used in the claimsand often, for clarity, a single substituent is shown attached to thecompound in place of multiple substituents which are allowed under thedefinitions of Formula I defined previously.

Schemes A-D provide general guidelines for making compounds of FormulaL. Scheme A illustrates the addition of the R¹ substituent on the4-azasteroidal backbone having an unsubstituted 2-position carbon.Scheme B illustrates the addition of the R¹ and the X substituents onthe 4-azasteroidal backbone at positions 4 and 2, respectively. Scheme Crepresents the general synthesis of compounds of Formula C-7. Scheme Dprovides a general guide for synthesis of compounds having substituentsR² and R³ on the methylene linker attached to the 4-azasteroidalbackbone at position 17. In the synthesizing compounds of formulas C-7and D-2, various commercially available amines can be used. It should benoted that in Schemes B and D, the selection of the particular leavinggroup, LG, will of course depend upon the particular substituent classthat is incorporated onto the core structure. Selection and applicationof leaving groups is a common practice in the synthetic organic chemicalart and this information is readily known and accessible to one skilledin the art. See for example, Organic Synthesis, Smith, M, McGraw-HillINC, 1994, New York. ISBN 0-074048716-2.

EXAMPLES

The compounds of the present invention can be prepared according to theprocedures denoted in the following reaction Schemes and Examples ormodifications thereof using readily available starting materials,reagents, and conventional procedures or variations thereof well-knownto a practitioner of ordinary skill in the art of synthetic organicchemistry. Specific definitions of variables in the Schemes are givenfor illustrative purposes only and are not intended to limit theprocedures described.

The following examples are provided to further illustrate details forthe preparation and use of the compounds of the present invention. Theyare not intended to be limitations on the scope of the instant inventionin any way, and they should not be so construed. Furthermore, thecompounds described in the following examples are not to be construed asforming the only genus that is considered as the invention, and anycombination of the compounds or their moieties can itself form a genus.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. All temperatures are in degreesCelsius unless noted otherwise.

The selective androgen receptor modulators (SARMs) of formula I wereprepared as outlined in Schemes 1, 2, 3, 4, and 5.

The selective androgen receptor modulators (SARMs) of structural formula1-6 were prepared as outlined in Scheme 1. The starting material was the17β-carboxylic acid 1-1 which is disclosed in G. H. Rasmusson et al., J.Med. Chem. 29: 2298-2315 (1986) and R. L. Tolman, et al., J. SteroidBiochem. Mol. Biol., 60: 303-309 (1997), each incorporated by reference,herein.

Example 1 Step A: 4 Methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carbinol(1-2)

To a solution of 1-1 (36.5 g, 110.12 mmol) in CH₂Cl₂:THF (1:1-500 mL) at0° C. was added Et₃N (20.0 mL, 143.2 mmol). iso-Butyl chloroformate(17.1 mL, 132.1 mmol) was added dropwise and after 30 mins the coolingbath was removed and the reaction was stirred for 2 hours. The reactionwas then cooled to 0° C. and a solution of 2 M LiBH₄ in THF (165.2 mL,330.4 mmol) was added dropwise. The reaction was stirred at 0° C. for 2hours. The reaction was quenched by dropwise addition of a saturatedsolution of NH₄Cl (125 mL), diluted with CH₂Cl₂ (900 mL), washed with 1N NaOH, brine, dried (MgSO₄) and then concentrated. The residue wasazeotroped with toluene and dried under high vacuum for 18 hours beforebeing used crude in next reaction (−2. MS calculated M+H: 318, found318.

Step B: 4-Methyl-3-oxo-4-aza-5α-androst-1-ene-17β-methyl tosylate (1-3)

To a solution of 1-2 (27.0 g crude, ca 85.0 mmol) in CH₂Cl₂ (250 mL) at0° C. was added pyridine (50 mL) and p-TosCl (26.0 g, 136.1 mmol). After30 minutes, the cooling bath was removed and the reaction was stirredfor 15 hours. The reaction was quenched by the addition of a saturatedsolution of NaHCO₃ (125 mL), diluted with CH₂Cl₂ (800 mL), washed withbrine, dried (MgSO₄) and then concentrated. The residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 1-3 asa white solid. MS calculated M+H: 472, found 472.

Step C: 4-Methyl-3-oxo-4-aza-5α-androst-1-ene-17μ-acetonitrile (1-4)

To a solution of 1-3 (43.0 g, 91 mmol) in DMSO (120 mL) at rt was addedNaCN (17.9 g, 365 mmol) slowly and the reaction was placed in an oilbath at 120° C. and stirred for 2 hours. After cooling, the reaction wasdiluted with CH₂Cl₂ (1000 mL), washed with a saturated solution ofNaHCO₃ (125 mL), brine, dried (MgSO₄) and then concentrated. The residuewas purified by chromatography on silica gel (0-100% EtOAc in hexanes)to afford 1-4 as a white solid. MS calculated M+H: 327, found 327.

Step D: 4-Methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetic acid (1-5)

To a solution of 1-4 (28.7 g, 87.9 mmol) in AcOH (50 mL) at rt was addedconc. HCl (50 mL) and the reaction was heated to 125° C. and stirred for14 hours. After cooling, the reaction was diluted with CH₂Cl₂ (800 mL),washed with cold water, a saturated solution of NaHCO₃, brine, dried(MgSO₄) and then concentrated. The residue was azeotroped with tolueneto afford 1-5 as a yellow foam. MS calculated M+H: 346, found 346.

Step E:N-[6-(Trifluoromethyl)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17βacetamide(1-7)

To a solution of 1-5 (1.00 g, 2.89 mmol) and HOAt (0.473 g, 3.47 mmol)in DMF (7.0 mL) was added EDC (0.67 g, 3.47 mmol) and the reaction wasstirred at room temperature. After one hour 3-amino-6-trifluoromethylpyridine (0.56 g, 3.47 mmol) was added and the reaction was heated to60° C. and stirred for 20 hours. After cooling, the reaction was dilutedwith EtOAc (500 mL), washed with cold water, brine, dried (MgSO₄) andthen concentrated. The residue was purified twice by chromatography onsilica gel (30-100% EtOAc in hexanes, 40:1 to 10:1 CH₂Cl₂:MeOH) toafford 1-7 as a white solid. MS calculated M+H: 490, found 490.

Example 2

Steps A-D are completed as described above for Example 1, followed by:

Step E:N-6-Methylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(2)

To a solution of 1-5 (2.50 g, 7.24 mmol) and HOAt (1.18 g, 8.68 mmol) inDMF (17.0 mL) was added EDC (1.66 g, 8.68 mmol) and the reaction wasstirred at room temperature. After 15 minutes, 3-amino-6-methylpyridine(0.82 g, 7.60 mmol) was added and the reaction was heated to 60° C. andstirred for 1 hour. The reaction was diluted with EtOAc (500 mL), washedwith cold water, brine, dried (MgSO₄) and then concentrated. The residuewas purified by chromatography on silica gel (20:1 to 10:1 CH₂Cl₂:MeOH)to afford 2 as a white solid. MS calculated M+H: 436, found 436.

Examples 3-103 in Table 1 were prepared in a similar manner as Examples1 and 2, but using the appropriate amine to generate the carboxamide.TABLE 1

Mass Spectrum Ex. NR²R³ Name Measured [M + H] 1

N-[6-(trifluoromethyl)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 490.2670 2

N-(6-methylpyridin-3-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.0 3

N-(5-methyl-1,3-thiazol-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 441.641 4

N-(2-chlorophenyl)-4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide455.045 5

N-(4,5-dimethyl-1,3-thiazol-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 455.668 6

N-(5-chloro-1,3-thiazol-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 462.059 7

N-(1,3-thiazol-2-yl)4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide428.0 8

N-(4-methyl-1,3-thiazol-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 442.0 9

N-[5-(trifluoroniethyl)-1,3,4- thiadiazol-2-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 497.0 10

N-(5-chloro-1,3-benzoxazol-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 496.0 11

N-(quinoxalin-6-yl)-4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide473.2914 12

N-(pyrazin-2-yl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide423.2761 13

N-(nicotinamid-6-yl)-4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide465.2854 14

N-(2-methyl-1,3-benzothiazol-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 492.2670 15

N-(4-cyanophenyl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide446.2790 16

N-(4-methylpyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.2972 17

N-(5-methylpyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.2966 18

N-(6-methylpyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.2970 19

N-(3-cyanophenyl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide446.2795 20

N-(5-chloropyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 456.2405 21

N-(6-aminopyridin-3-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 437.2909 22

N-(4-methylpyrimidin-2-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 437.2919 23

N-(3-methyl-1,2,4-thiadiazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 443.2478 24

N-[5-(trifluoromethyl)pyridin-2-yl]-4-methyl-3-oxo4-aza-5α-androst-1-en- 17β-acetamide 490.2668 25

N-(4-nitro-1H-imidazol-5-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β3-acetamide 456.2510 26

N-(6-aminopyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-andxost-1-en-17β-acetamide 437.2918 27

N-(3-ethyl-6-methylpyridin-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 464.3291 28

N-(4-methoxy-6-methylpyrimidin-2- yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 467.3026 29

N-(5-bromo-6-methylpyridin-2-yl)-4- methyl-3-oxo-4-aza-5z-androst-1-en-17β-acetamide 514.2086 30

N-(1H-benzimidazol-2-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 461.2918 31

N-(1H-pyrazol-3-yl)-4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide411.2763 32

N-(5-fluoropyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 440.2711 33

N-(4,6-dimethylpyridin-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 450.3115 34

N-(1-oxidopyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 438.2751 35

N-(pyridin-2-yl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide422.27977 36

N-(6-ethylpyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 450.3136 37

N-(pyridin-4-yl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide422.2805 38

N-(pyridin-3-yl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide422.2798 39

N-(6-aminopyridin-3-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 437.0 40

N-[6-(acetylamino)pyridin-3-yl]-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 479.0 41

N-(methyl 5-pyridin-2-ylcarbamate)- 4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 495.0 42

N-[(pyridin-5-yl)-2,2- dimethylpropanamid-2-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β- acetamide 521.0 43

N-[6-(formylamino)pyridin-3-yl]-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 465.0 44

N-(6-methoxypyridin-3-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 452.291 45

N-(1H-imidazol-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 411.2746 46

N-(6-cyanopyridin-3-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 447.2708 47

N-(3-methylisoxazol-5-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 426.2756 48

N-(5-methylisoxazol-3-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 426.2748 49

N-(2-chloropyridin-4-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 456.2412 50

N-(5-tert-butylisoxazol-3-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 468.3217 51

N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst- 1-en-17β-acetamide 469.2633 52

N-(2,6-dimethoxypyridin-3-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 482.3004 53

N-(6-chloropyridin-3-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 456.0 54

N-(4-chlorophenyl)-4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide455.2471 55

N-(3-chlorophenyl)-4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide455.2475 56

N-(3,5-difluorophenyl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 457.2659 57

N-(4-methylphenyl)-4-methyl-3-oxo- 4-aza-5α-androst-1-en-17β-acetamide435.3004 58

N-(3-methoxyphenyl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β- acetamide451.2958 59

N-(2,6-difluorophenyl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 457.2655 60

N-(3-fluorophenyl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide439.275 61

N-(4-fluorophenyl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide439.2749 62

N-[3-(trifluoromethyl)phenyl]-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 489.2718 63

N-(4-methoxyphenyl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β- acetamide451.296 64

N-[4-(trifluoromethyl)phenyl]-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 489.2713 65

N-[4-(trifluoromethoxy)phenyl]-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 505.2676 66

N-(phenyl)-4-methyl-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 420.6 67

N-(3-methylpyridin-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.0 68

N-[(2-carboxamidyl)pyridin-5-yl]-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 465.0 69

N-(2-aminopyrimidin-5-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 438.0 70

N-(4-aminopyrimidin-5-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 438.0 71

N-(3,5-dichloropyridin-4-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 491.0 72

N-(3-methoxypyridin-4-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 452.0 73

N-(3-methylpyridin-4-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.0 74

N-(3-aminopyridin-4-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 437.0 75

N-[(3-trifluoromethoxy)pyridin-4-yl]- 4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 490.0 76

N-(6-ethylpyridin-3-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 450.0 77

N-(6-oxo-1,6-dihydropyridin-3-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 438.0 78

N-(2-methylquinolin-4-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 486.0 79

N-(2-amino-4-methylcarboxyl- phenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 494.2 80

N-(2-aminopyrid-3-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 437.2 81

N-(2-amino-5-fluorophenyl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 454.2 82

N-(2-amino-3-methyl-phenyl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 450.2 83

N-(2-amino-4-trifluoromethylphenyl)- 4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 504.2 84

N-(2-amino-4-methoxyphenyl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 466.2 85

N-(2-amino-5-chlorophenyl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 471.2 86

N-(2-amino-5-methylphenyl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 450.2 87

N-(2-aminophenyl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide434.2 88

N-(6-methyl-4-aminopyrimid-5-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 452.6 89

N-(3-amino-5-trifluoromethylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst- 1-en-17β-acetamide 505.6 90

N-(3-amino-4,6-dimethyl-5- chloropyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 500.2 91

N-(2-amino-4,6-dimethylpyrid-3-yl)- 4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 465.6 92

N-(3-amino-4-methylpyrid-2-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 434.2 93

N-(6-methylpyrid-2-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.6 94

N-(pyrimid-5-yl)-4-methyl-3-oxo-4- aza-5α-androst-1-en-17β3-acetamide423.6 95

N-(2-methylpyrimid-5-yl)-4-methyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 437.6 96

N-(2-amino-3- methoxycarbonylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β- acetamide 494.6 97

N-(1,3-dioxo-2,3-dihydro-1H- isoindol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 490.6 98

N-(3-carboxamidophenyl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 464.6 99

N-(4-carboxamidophenyl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 464.6 100

N-(2-amino-6-methylpyrid-3-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 451.6 101

N-(2,6-diaminopyrid-3-yl)-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 452.6 102

N-(2-amino-5-methoxycarbonyl- pyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 495.6 103

N-(2-amino-5-methylpyrid-3-yl)-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 451.6

The selective androgen receptor modulators (SARMs) of structural formula2-8 were prepared as outlined in Scheme 2. The starting material was themethyl 17β-carboxylate 2-1 which is disclosed in G. H. Rasmusson et al.,J. Med. Chem., 29: 2298-2315 (1986).

Example 104 Step A: Methyl4-p-methoxybenzyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylate (2-2)

To a solution of 2-1 (10.0 g, 30.2 mmol) in THF (300 mL) at rt was addedNaH (2.2 g, 45.3 mmol, 60% dispersion in mineral oil) and the resultingmixture was stirred for 30 mins. p-Methoxybenzyl chloride (6.4 mL, 45.3mmol) and n-Bu₄NI (ca. 0.5 g) were added and the reaction was heated toreflux and stirred for 4 hours. The reaction was then cooled to roomtemperature and the reaction was quenched by the dropwise addition of 1NHCl. The mixture was concentrated and the precipitate was collected andwashed with H₂O and hexanes. The yellow solid 2-2 was dried under highvacuum for 18 hours. MS calculated M+H: 452, found 452.

Step B: 4-Methoxybenzyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylic acid(2-3)

To a solution of 2-2 (13.6 g, 30.1 mmol) in dioxane (200 mL) at roomtemperature was added LiOH.H₂O (2.5 g, 60.2 mmol) and the reaction washeated to reflux and stirred for 4 hours. The reaction was cooled toroom temperature and then concentrated. The residue was diluted with a 1N solution of HCl and the precipitate was collected and washed with H₂Oand hexanes to afford 2-3 as a white solid.

MS calculated M+H: 438, found 438.

Step C: 4-p-Methoxybenzyl-3-oxo-aza-5α-androst-1-ene-17β-carbinol (2-4)

To a solution of 2-3 (13.1 g, 29.4 mmol) in CH₂Cl₂:THF (1:1-300 mL) at0° C. was added Et₃N (5.4 mL, 39.0 mmol). iso-Butyl chloroformate (4.7mL, 36.0 mmol) was added dropwise and after 30 minutes the cooling bathwas removed and the reaction was stirred for 2 hours. The reaction wasthen cooled to 0° C. and a solution of 2 M LiBH₄ in THF (43.5 mL, 87.0mmol) was added dropwise. The reaction was stirred at 0° C. for 2 hours.The reaction was quenched by dropwise addition of a saturated solutionof NH₄Cl (125 mL), diluted with CH₂Cl₂ (900 mL), washed with 1 N NaOH,brine, dried (MgSO₄) and then concentrated. The residue was dissolved ina small amount of CH₂Cl₂ and triturated with Et₂O. The solid wasfiltered and washed with hexanes to afford 2-3 as a white solid. MScalculated M+H: 424, found 424.

Step D: 4-p-Methoxybenzyl-3-oxo-aza-5α-androst-1-ene-17β-methyl tosylate(2-5)

To a solution of 2-4 (45.0 g, 106.2 mmol) in CH₂Cl₂ (500 mL) at 0° C.was added pyridine (100 mL) and p-TosCl (32.6 g, 170 mmol). After 30minutes, the cooling bath was removed and the reaction was stirred for15 hours. LCMS shows that the reaction is complete. The reaction wasquenched by the addition of a saturated solution of NaHCO₃ (125 mL),diluted with CH₂Cl₂ (800 mL), washed with brine, dried (MgSO₄) and thenconcentrated. The residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to afford 2-5 as a white waxy solid. MScalculated M+H: 578, found 578.

Step E: 4-p-Methoxybenzyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetonitrile(2-6)

To a solution of 1-3 (20.0 g, 34.6 mmol) in DMSO (120 mL) at roomtemperature was added NaCN (4.2 g, 86.5 mmol) and the reaction wasplaced in an oil bath at 95° C. and stirred for 2 hours. After cooling,the reaction was diluted with CH₂Cl₂ (800 mL), washed with a saturatedsolution of NaHCO₃ (125 mL), brine, dried (MgSO₄) and then concentrated.The residue was purified by chromatography on silica gel (0-100% EtOAcin hexanes) to afford 2-6 as a white solid. MS calculated M+H: 327,found 327.

Step F: 3-Oxo-4-aza-5α-androst-1-ene-175-acetic acid (2-7)

To a solution of 2-6 (7.8 g, 18.0 mmol) in AcOH (50 mL) at rt was addedconc. HCl (50 mL) and the reaction was heated to 125° C. and stirred for14 hours. After cooling, the reaction was diluted with CH₂Cl₂ (800 mL),washed with cold water, a saturated solution of NaHCO₃, brine, dried(MgSO₄) and then concentrated. The residue was azeotroped with tolueneto afford 2-7 as a yellow foam. MS calculated M+H: 332, found 332.

Step G:N-[5-(Methyl)-pyridin-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(2-9)

To a solution of 2-7 (0.125 g, 0.38 mmol) and HOAt (1.0 mL, 0.50 mmol,0.5 M in DMF) in DMF (1.0 mL) was added EDC (0.94 g, 0.50 mmol) and thereaction was stirred at room temperature. After one hour,2-amino-5-picoline (0.53 g, 0.50 mmol) was added and the reaction washeated to 60° C. and stirred for 16 hours. After cooling, the reactionwas concentrated. The residue was purified by flash chromatography onsilica gel (0-100% EtOAc in hexanes) to afford 2-9 as a white solid. MScalculated M+H: 422, found 422.

Examples 106-195 Table 2 were prepared in a similar manner as Example104, but using the appropriate amine to generate the carboxamide. TABLE2

Mass spectrum Ex. NR²R³ Name Measured [M + H] 104

N-(5-methylpyridin-2-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide422.2 105

N-[(4,6-dimethyl)-pyrid-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 436.2 106

N-(tetrazol-5-yl)-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 399.2 107

N-(pyridin-3-yl)-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 408.2 108

N-(5-methyl-1,2-isothiazol-3-yl)-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 428.2 109

N-(5-methyl-1,2-thiazol-3-yl)-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 412.2 110

N-(2-methyl-pyrid-4-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide 422.2111

N-[(5-trifluoromethyl)-pyrid-2-yl]- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 476.2 112

N-[((6-trifluoromethyl)-pyrid-3-yl]- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 476.2 113

N-(4-methyl-1,3-thiazol-2-yl)-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 428.3 114

N-(5-methyl-1,3-thiazol-2-yl)-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 428.2 115

N-(1H-indazol-6-yl)-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 447.2 116

N-(imidazol-2-yl)-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 397.2 117

N-(pyrazol-3-yl)-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 397.3 118

N-(5-methylpyrazol-3-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide412.2 119

N-[2,6-dimethyl)-1,3-pyrimid-4- yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 409.2 120

N-(1,3-pyrazin-4-yl)-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 409.2121

N-(4-methyl-1,3-pyrimid-2-yl)-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 423.2 122

N-(1,3-pyrimid-2-yl)-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 447.2123

N-(benzimidazol-2-yl)-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 447.2124

N-[(3-carboxamido)-pyridin-6-yl]- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 451.2 125

N-(5-fluoropyrimid-2-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide423.2 126

N-(pyrid-4-yl)-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 408.3 127

N-(3-methylpyrid-2-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide 422.2128

N-(4-methylpyrid-2-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide 422.2129

N-(6-methylpyrid-2-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide 422.2130

N-(4,5-dimethylisoxazol-2-yl)-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 426.2 131

N-[(5-carboxyl)-pyrid-2-yl]-3-oxo- 4-aza-5α-androst-1-en-17β- acetamide452.2 132

N-(5-cyanopyrid-2-yl)-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 433.2133

N-[5-(mopholin-4-ylcarbonyl)pyrid- 2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 521.2 134

N-[5-(piperizin-1-ylcarbonyl)pyrid- 2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 520.2 135

N-[5-(pyrollidin-1- ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 505.2 136

N-[5-(diamin-1- ylethylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β- acetamide 493.2 137

N-[5-(histaminylcarbonyl)pyrid-2- yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 545.2 138

N-{5-[(2- ethylamino)ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1- en-17β-acetamide 522.2 139

N-{5-[(1- hydroxymethyl)propylaminocar-bonyl]pyrid-2-yl)-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 523.2 140

N-{5-[(2- methoxyethyl)aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 509.2 141

N-{5-[2- (piperizinyl)ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1- en-17β-acetamide 563.2 142

N-{5-[3-(morphilino)propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 578.2 143

N-{5-[2- (morphilino)ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1- en-17β-acetamide 564.2 144

N-{5-[(3- dimethylamino)propylaminocar-bonyl]pyrid-2-yl}-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 536.2 145

N-[5-(methoxycarbonyl)pyrid-2-yl]- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 466.2 146

N-[5-(ethoxycarbonyl)pyrid-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 479.6 147

N-[5-(isopropoxycarbonyl)pyrid-2- yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 494.2 148

N-[(5-cyano-4,6-dimethyl)pyrid-2- yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 461.2 149

N-[(5-bromo-6-methyl)pyrid-2-yl]- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 501.2 150

N-{5-[methylaminocarbonyl]pyrid- 2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 465.6 151

N-{5- [dimethylaminocarbonyl]pyrid-2- yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 479.6 152

N-{5-[N-(2-methoxyethyl)-N- methyl-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β- acetamide 523.7 153

N-{5-[N-(dimethylaminoethyl)-N- methyl-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β- acetamide 536.7 154

N-[5-(ethoxycarbonyl)-4-methyl- pyrimid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 495.6 155

N-[4-(ethoxycarbonyl)-1,3-thiazol- 2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 486.7 156

N-[(6-methyl)pyrid-3-yl]-3-oxo-4- aza-5α-androst-1-en-17β-acetamide422.6 157

N-[4-(carboxyl)-1,3-thiazol-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 458.6 158

N-[4-(carboxamido)-1,3-thiazol-2- yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 457.6 159

N-[4-(N,N- dimethylaminocarbonyl)-1,3- thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 528.7 160

N-[(N,N- dimethylamino)ethylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 528.7 161

N-[4-(N-methylaminocarbonyl)-1,3- thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 471.6 162

N-[5-(carboxamido)-1H-imidazol-4- yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 440.6 163

N-[2-(ethoxycarbonyl)-1-methyl- 1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 483.6 164

N-[2-(carboxamido)-1-methyl-1H- imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 454.6 165

N-[2-(carboxyl)-1-methyl-1H- imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 455.6 166

N-[2-(N-methylamino carbonyl)-1- methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 477.6 167

N-[2-(N,N-dimethylamino carbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 482.6 168

N-[5- (hydroxylaminocarbonyl)pyrid-2- yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 467.6 169

N-[5-(1H-tetrazol-5-yl)pyrid-2-yl]- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 476.6 170

N-[6-aminopyrid-2-yl]-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 423.6171

N-(2,3′-bipyridin-6′-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide485.6 172

N-[5-(1H-pyrazol-5-yl)pyrid-2-yl]- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 486.6 173

N-[5-(pyrimidin-5-yl)pyrid-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 486.6 174

N-[5-(pyrimidin-2-yl)pyrid-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 486.6 175

N-[5-(pyrazin-2-yl)pyrid-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 486.6 176

N-[5-(2-furyl)pyrid-2-yl]-3-oxo-4- aza-5α-androst-1-en-17β-acetamide474.6 177

N-(3,3′-bipyridin-6′-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide485.6 178

N-[6-bromopyrid-2-yl]-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 487.5179

N-[5-bromopyrid-2-yl]-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 487.5180

N-(3,3′-bipyridin-6′-yl)-3-oxo-4- aza-5α-androst-1-en-17β-acetamide485.6 181

N-[6-(pyrimidin-5-yl)pyrid-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 485.6 182

N-{6- [(aminocarbonyl)amino]pyrid-2- yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 466.5 183

N-{6-[(N-methyl- aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β- acetamide 480.6 184

N-{6-[(N,N-dimethyl- (aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β- acetamide 494.6 185

N-{6-[({[2- (dimethylamino)ethyl]amino}car-bonyl)amino]pyrid-2-yl}-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 537.6186

N-{6-[({[2-(N- piperidinyl)ethyl]amino}carbonyl)amino]pyrid-2-yl)-3-oxo-4-aza-5α- androst-1-en-17β-acetamide 577.7 187

N-{6-[({[2-morpholin-4- ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 579.7 188

N-{6- [dimethylaminocarbonyl]pyrid-2- yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 479.7 189

N-{4-methyl-5- [dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 493.6 190

N-{6-[carboxamido]pyrid-2-yl}-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 451.6 191

N-(6-(pyrizin-2-yl)pyrid-2-yl]-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 486.6 192

N-{5-[(phenylsulfonyl]pyrid-2-yl}- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 548.7 193

N-{5-[(sulfonamido]pyrid-2-yl}-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 487.6 194

N-{5-sulfopyrid-2-yl)-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide 488.6195

N-{5-[N-(diaminomethylene)- carbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 493.6

The selective androgen receptor modulators (SARMs) of structural formula3-5 were prepared as outlined in Scheme 3. The synthesis of the startingmaterial, the 2-fluoro-17β-carboxylic acid 3A-4, is presented in Scheme3A. In Scheme 3A, the starting material was the 17β-carboxylate, 3A-1,which is disclosed in G. H. Rasmusson et al., J. Med. Chem., 27:1690-1701 (1984), incorporated by reference, herein.

Synthesis of Starting Material 3A-4

Step A: 2α-Fluoro-4-methyl-3-oxo-4-aza-5α-androstane-17β-carboxylic acidmethyl ester (3A-2)

To a solution of 3A-1 (7.5 g, 21.6 mmol) in THF (100 mL) at −78° C. wasadded a solution of 1.5 M LDA in THF (17.3 mL, 25.9 mmol) dropwise over20 minutes and then stirred 1 hour. A solution of FN(SO₂Ph)₂ (10.2 g,32.4 mmol) in THF (40 mL) was then added over 20 minutes. After 30minutes, the cooling bath was removed and the reaction was stirred for14 hours. Et₂O was added, and the mixture was washed with water,saturated aqueous sodium hydrogencarbonate, brine, dried (MgSO₄) andthen concentrated. Chromatography on silica gel (hexanes to EtoAc aseluent) gave 3A-2 as a colorless solid. MS calculated M+H: 366, found366.1.

Step B: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylicacid methyl ester (3A-3)

To a solution of 3A-2 (30 g, 82.1 mmol) in THF (400 mL) at −78° C. wasadded a solution of 1.5 M LDA in THF (71.1 mL, 107 mmol) dropwise over30 minutes and then stirred 1 hour. Methyl benzenesulfinate (19.23 g,123 mmol) was then added over 15 min. After 30 minutes, the cooling bathwas removed and the reaction was stirred for 1 hour. Et₂O was added, andthe mixture was washed with water, saturated aqueous sodiumhydrogencarbonate, brine, dried (MgSO₄) and then concentrated. Theresidue was dissolved in toluene (200 mL) and heated at reflux for 2hours. Solvent evaporation and chromatography of the residue on silicagel (hexanes to 50% EtOAc/hexanes as eluent) gave 3A-3 as a pale yellowsolid. MS calculated M+H: 364, found 364.1.

Step C: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxylicacid (3A-4)

To a solution of 3A-3 (2.4 g, 6.6 mmol) in 1,4-dioxane (50 mL) was addeda solution of lithium hydroxide (0.41 g, 9.9 mmol) in water (20 mL), andthe mixture heated at 100° C. for 3 hours. After cooling, the mixturewas diluted with ethyl acetate and then washed with 1N HCl, brine, dried(MgSO₄) and then concentrated to give 3A-4 (2.2 g) as a pale yellowsolid. MS calculated M+H: 350, found 350.

Example 196 Step A:2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-carbinol (3-1)

To a solution of 3A-4 (2.0 g, 5.7 mmol) in CH₂Cl₂:THF (1:1-100 mL) at 0°C. was added Et₃N (1.0 mL, 7.4 mmol). iso-Butyl chloroformate (0.89 mL,6.8 mmol) was added dropwise and after 30 minutes the cooling bath wasremoved and the reaction was stirred for 2 hours. The reaction was thencooled to 0° C. and a solution of 2 M LiBH₄ in THF (8.6 mL, 17.2 mmol)was added dropwise. The reaction was stirred at 0° C. for 2 hours. Thereaction was quenched by dropwise addition of a saturated solution ofNH₄Cl (25 mL), diluted with CH₂Cl₂ (200 mL), washed with 1 N NaOH,brine, dried (MgSO₄) and then concentrated. The residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 3-1 asa white solid. MS calculated M+H: 336, found 336.

Step B: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-methyltosylate (3-2)

To a solution of 3-1 (1.0 g, 2.9 mmol) in CH₂Cl₂ (10 mL) at 0° C. wasadded pyridine (2 mL) and p-TosCl (0.74 g, 3.9 mmol). After 30 minutes,the cooling bath was removed and the reaction was stirred for 15 hours.LCMS shows that the reaction is complete. The reaction was quenched bythe addition of a saturated solution of NaHCO₃ (5 mL), diluted withCH₂Cl₂ (200 mL), washed with brine, dried (MgSO₄) and then concentrated.The residue was purified by chromatography on silica gel (0-100% EtOAcin hexanes) to afford 3-2 as a white waxy solid. MS calculated M+H: 490,found 490.

Step C: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetonitrile(3-3)

To a solution of 3-2 (1.37 g, 2.8 mmol) in DMSO (20 mL) at roomtemperature was added NaCN (0.69 g, 14.0 mmol) slowly and the reactionwas placed in an oil bath at 105° C. and stirred for 2 hours. Aftercooling, the reaction was diluted with CH₂Cl₂ (100 mL), washed with asaturated solution of NaHCO₃ (15 mL), brine, dried (MgSO₄) and thenconcentrated. The residue was purified by chromatography on silica gel(0-100% EtOAc in hexanes) to afford 3-3 as a white solid. MS calculatedM+H: 345, found 345.

Step D: 2-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetic acid(3-4)

To a solution of 3-3 (0.75 g, 2.2 mmol) in AcOH (15 mL) at rt was addedconc. HCl (15 mL) and the reaction was heated to 125° C. and stirred for14 hours. After cooling, the reaction was diluted with CH₂Cl₂ (200 mL),washed with cold water, a saturated solution of NaHCO₃, brine, dried(MgSO₄) and then concentrated. The residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 34 as awhite solid. MS calculated M+H: 364, found 364.

Step E:N-[6-(Trifluoromethyl)pyridin-3-yl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(3-61

To a solution of 3-4 (0.105 g, 0.29 mmol) and HOAt (0.047 g, 0.35 mmol)in DMF (1.0 mL) was added EDC (0.067 g, 0.35 mmol) and the reaction wasstirred at room temperature. After one hour3-amino-6-trifluoromethylpyridine (0.056 g, 0.35 mmol) was added and thereaction was heated to 60° C. and stirred for 20 hours. After cooling,the reaction was diluted with EtOAc (100 mL), washed with cold water,brine, dried (MgSO₄) and then concentrated. The residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 36 as awhite solid. MS calculated M+H: 508, found 508.

Example 197 in Table 3 was prepared in a similar manner as Example 196,but using the appropriate amine to generate the carboxamide. TABLE 3

Mass Spectrum Ex. NR²R³ Name Measured [M + H] 196

N-(6-(trifluoromethyl)pyridin-3-yl)- 2-fluro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 508.3 197

N-(6-methylpyridin-3-yl)-2-fluoro-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 454.5

The selective androgen receptor modulators (SARMs) of structural formula4-4 were prepared as outlined in Scheme 4. The starting material was the17β-acetic acid 1-5 that was prepared in Scheme 1.

Example 198 Step A:21-Methyl-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetate (4-1)

A solution of 1-5 (3.0 g, 9.1 mmol) in MeOH:AcOH (2:1-22.5 mL) washeated to 55° C. and stirred for 18 hours. The reaction was then cooledto room temperature, diluted with CH₂Cl₂ (900 mL), and washed with H₂Oand brine, dried (MgSO₄) and then concentrated. The residue was purifiedby chromatography on silica gel (0-100% EtOAc in hexanes) to afford 4-1as a white solid. MS calculated M+H: 360, found 360.

Step B:20-Fluoro-21-methyl-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetate(4-2)

To a solution of 4-1 (0.75 g, 2.8 mmol) in anhydrous THF (11 mL) at −78°C. was added hexamethylphosphorous triamide (0.25 mL, 1.39 mmol).Lithium diisopropylamide ono(tetrahydrofuran) complex (2.8 mL, 4.17mmol, 1.5 M solution in THF) was then added dropwise and the reactionwas stirred at −78° C. for 15 minutes. N-fluoro-benzenesulfonamide (1.32g, 4.27 mmol, dissolved in 1.5 mL of THF) was then added dropwise andthe reaction was allowed to warm to room temperature and stirred for 4hours. The reaction was quenched by the addition of a saturated solutionof NH₄Cl (25 mL), diluted with CH₂Cl₂ (200 mL), washed with brine, dried(MgSO₄) and then concentrated. The residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 4-2 asa yellow oil. MS calculated M+H: 378, found 378.

Step C: 20-Fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetic acid(4-3)

To a solution of 4-2 (0.79 g, 2.09 mmol) in dioxane (7 mL) at roomtemperature was added LiOH monohydrate (0.26 g, 6.28 mmol) dissolved inH₂O (2 mL) and the reaction was allowed to stir at room temperature for18 hours. The reaction was acidified with 1 N HCl to pH 5 and thenextracted with CH₂Cl₂ (200 mL), washed with brine, dried (MgSO₄) andthen concentrated to afford 4-3 as a white solid. MS calculated M+H:364, found 364.

Step D:N-[6-(Trifluoromethyl)pyridin-3-yl]-20-fluoro-4-methyl-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(4-5)

To a solution of 4-3 (0.05 g, 0.14 mmol) and HOAt (0.024 g, 0.18 mmol)in dichloroethane (2.0 mL) was added EDC (0.034 g, 0.18 mmol) and3-amino-trifluoromethylpyridine (0.029 g, 018 mmol) was added and thereaction was stirred for 2 hours. The reaction was concentrated and theresidue was purified by chromatography on silica gel (0-100% EtOAc inhexanes) to afford 4-5 as a white solid. MS calculated M+H: 508, found508.

Examples 199-227 in Table 4 were prepared in a similar manner as Example198, but using the appropriate amine to generate the carboxamide. TABLE4

Mass spectrum Ex. NR²R³ Name Measured [M + H] 198

N-(6-(trifluoromethyl)pyridin-3-yl)- 20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 508.2556 199

N-(pyridin-3-yl)-20-fluoro-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 440.2701 200

N-(pyridin-2-yl)-20-fluoro-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 440.2702 201

N-(pyridin-4-yl)-20-fluoro-4-methyl- 3-oxo-4-aza-5i-androst-1-en-17β-acetamide 440.2721 202

N-(4-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 454.2892 203

N-(6-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 454.2884 204

N-(5-chloropyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 475.2 205

N-(6-fluoropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 458.2588 206

N-(6-methoxypyridin-3-yl)-20-fluoro- 4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 470.2796 207

N-(6-chloropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 474.2299 208

N-(6-methylpyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 454.2865 209

N-(3-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 454.2863 210

N-(6-cyanopyridin-3-yl)-20-fluoro-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 465.2634 211

N-(5-trifluromethylpyridin-2-yl)-20- fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 508.6 212

N-(5-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 454.6 213

N-(5-fluoropyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 458.6 214

N-(1,3-thiazol-2-yl)-20-fluoro-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 446.6 215

N-(1,3-pyrimid-4-yl)-20-fluoro-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 441.6 216

N-(pyrizin-2-yl)-20-fluoro-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 441.6 217

N-(2-chloropyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 475.0 218

N-(2,6-dichloropyridin-4-yl)-20- fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 509.5 219

N-(2-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 454.6 220

N-(3-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 454.6 221

N-(5-cyanopyridin-2-yl)-20-fluoro-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 464.6 222

N-(5-chloro-1,3-benzoxazol-2-yl)-20- fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 515.6 223

N-(5-methylisoxazol-3-yl)-20-fluoro- 4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 444.6 224

N-(imidazol-2-yl)-20-fluoro-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 429.6 225

N-(pyrazol-3-yl)-20-fluoro-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 429.6 226

N-(6-carboxamidopyridin-3-yl)-20- fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 483.6 227

N-methyl-N-(3-methylpyridin-4-yl)- 20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 468.6

The selective androgen receptor modulators (SARMs) of structural formula5-5 were prepared as outlined in Scheme 5. The starting material was themethyl-17β-acetate 4-1 which is prepared in Scheme 4.

Example 228 Step A:20-Hydroxy-21-methyl-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetate(5-1)

To a solution of 4-1 (0.75 g, 2.1 mmol) in anhydrous THF (30 mL) at −78°C. was added dropwise potassium bis(trimethylsilyl)amide (10.43 mL, 5.21mmol, 0.5 M solution in toluene) and the reaction was stirred at −78° C.for 30 minutes. (1S)-(+)-10-Camphorfulfonyl)-oxaziridine (1.19 g, 5.21mmol, dissolved in 10 mL of THP) was added dropwise and the reaction wasstirred for 4 hours at −78° C. The reaction was quenched by the additionof a saturated solution of NH₄Cl (25 mL), diluted with CH₂Cl₂ (200 mL),washed with brine, dried (MgSO₄) and then concentrated. The residue waspurified by chromatography on silica gel (0-100% EtOAc in hexanes) toafford 5-1 as a white solid. MS calculated M+H: 376, found 376.

Step B: 20-Hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetic acid(5-2)

To a solution of 5-1 (0.19 g, 0.51 mmol) in dioxane (2 mL) at rt wasadded LiOH monohydrate (0.038 g, 1.0 mmol) dissolved in H₂O (20.5 mL)and the reaction was allowed to stir at room temperature for 18 hours.The reaction was acidified with 1 N HCl to pH 5 and then extracted withCH₂Cl₂ (200 mL), washed with brine, dried (MgSO₄) and then concentratedto afford 5-2 as a white solid. MS calculated M+H: 362, found 362.

Step C: 20-Acetoxy-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetic acid(5-3)

To a solution of 5-2 (0.17 g, 0.468 mmol) in CH₂Cl₂ (2 mL) at roomtemperature was added Ac₂O (0.05 mL, 0.561 mmol), Et₃N (0.10 mL, 0.102mmol) and DMAP (0.06 g, 0.46 mmol) and the reaction was allowed to stirat room temperature for 3 hours. The reaction was quenched by theaddition of H₂O (5 mL), diluted with CH₂Cl₂ (50 mL), washed with brine,dried (MgSO₄) and then concentrated. The residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 5-3 asa white solid. MS calculated M+H: 404, found 404.

Step D:N-(Pyridin-3-yl)-20-acetoxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(5-6

To a solution of 5-3 (0.05 g, 0.14 mmol) and HOAt (0.024 g, 0.18 mmol)in dichloroethane (2.0 mL) was added EDC (0.034 g, 0.18 mmol) and3-aminopyridine (0.029 g, 018 mmol) and the reaction was stirred for 2hours. The reaction was concentrated and the residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 5-6 asa white solid. MS calculated M+H: 480, found 480.

Step C:N-(Pyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(5-7)

To a solution of 5-6 (0.04 g, 0.03 mmol) in MeOH (1 mL) at roomtemperature was added K₂CO₃ (0.02 g, 0.03 mmol) and the reaction wasallowed to stir at room temperature for 18 hours. The reaction wasacidified with 1 N HCl to pH 5 and then extracted with CH₂Cl₂ (200 mL),washed with brine, dried (MgSO₄) and then concentrated to afford 5-7 asa white solid. MS calculated M+H: 438, found 438.

Examples 229-230 in Table 5 was prepared in a similar manner as Example228, but using the appropriate amine to generate the carboxamide. TABLE5

Mass spectrum Ex. NR²R³ Name Measured [M + H] 228

N-(pyridin-3-yl)-20-hydroxy-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 440.2 229

N-(pyridin-4-yl)-20-hydroxy-4-methyl- 3-oxo-4-aza-5α-androst-1-en-17β-acetamide 438.2 230

N-(2-aminopyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en- 17β-acetamide 453.6

The selective androgen receptor modulators (SARMs) of structural formula6-2 were prepared as outlined in Scheme 6. The starting material was the17βacetic acid 6-1 was prepared in an analogous manner as 2-6 asdescribed in Scheme 2, except that ethyliodide was used instead ofp-methoxybenuzylchloride.

Examples 231-242 in Table 6 were prepared in a similar manner asExamples 1 and 2, but using acid 6-1 and the appropriate amine togenerate the acetamide. TABLE 6

Mass spectrum Ex. NR²R³ Name Measured [M + H] 231

N-[5-methylpyridin-2-yl]-4-ethyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 450.6 232

N-(2-amino-4-methoxycarbonyl- phenyl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 508.7 233

N-(pyridin-2-yl)-4-ethyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide436.6 234

N-(pyridin-3-yl)-4-ethyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide436.6 235

N-(pyridin-4-yl)-4-ethyl-3-oxo-4- aza-5α-androst-1-en-17β-acetamide436.6 236

N-(5-carboxamidopyridin-2-yl)-4- ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 479.6 237

N-(pyrizin-2-yl)-4-ethyl-3-oxo-4-aza- 5α-androst-1-en-17β-acetamide437.6 238

N-(5-fluoropyridin-2-yl)-4-ethyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 454.6 239

N-(6-aminopyridin-2-yl)-4-ethyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 451.6 240

N-(5-cyclopropyl-1,3,4-thiadiazol-2- yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 483.7 241

N-(4,5-dimethyl-1,3-thiazol-2-yl)-4- ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 470.7 242

N-(6-methylpyridin-2-yl)-4-ethyl-3- oxo-4-aza-5α-androst-1-en-17β-acetamide 450.7

The selective androgen receptor modulators (SARMs) of structural formula7-4 were prepared as outlined in Scheme 7. The starting material was themethyl-17β-acetate 41 which is prepared in Scheme 4.

Example 243 Step A:20-Azido-21-methyl-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetate(7-1)

To a solution of the ester 4-1 (1.75 g, 4.87 mmoles) in 1% HMPA in THF(10 mL) at −78° C. was added dropwise a solution of potassiumhexamethyldisilazide (19.5 mL, 9.74 mmoles, 0.5 M in toluene). After 20minutes 2,4,6-triisopropylbenzene sulfonylazide (2.26 g, 7.30 mmoles)was added and the reaction was stirred for an additional 20 minutes.Acetic acid (0.60 mL) was then addition and the cooling bath wasremoved. After stirring for 18 hours at 25° C., the reaction wasquenched by the addition of a H₂O (50 mL), diluted with CH₂Cl₂ (200 mL),washed with brine, dried (MgSO₄) and then concentrated. The residue waspurified by chromatography on silica gel (30:1 to 10:1 methylenechloride: MeOH gradient) to afford 7-1 as a white solid. MS calculatedM+H: 401, found 401.

Step B: 20-Azido-4-methyl-3-oxo-4-aza-5α-androst-1-ene-17β-acetic acid(7-2)

To a solution of the azido ester 7-1 (1.67 g, 4.17 mmoles) in methanol(15 mL) was added aqueous sodium hydroxide solution (5 N, 7.5 mL). Afterstirring at room temperature for two hours, the reaction wasconcentrated under reduced pressure to remove most of the methanol. Thereaction was acidified with 1 N HCl to pH 5 and the resultingprecipitate was collected by filtration. The solids were washed withwater and air dried to afford the 20-azido acid 7-2 as a white solid. MScalculated M+H: 387, found 387.

Step C:N-(Pyridin-4-yl)-20-azido-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(7-5)

To a solution of 7-2 (0.05 g, 0.14 mmol) and HOAt (0.024 g, 0.18 mmol)in dichloroethane (2.0 mL) was added EDC (0.034 g, 0.18 mmol) and3-aminopyridine (0.029 g, 018 mmol) and the reaction was stirred for 2hours. The reaction was concentrated and the residue was purified bychromatography on silica gel (0-100% EtOAc in hexanes) to afford 7-5 asa white solid. MS calculated M+H: 463, found 463.

Step D:N-(Pyridin-4-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide(7-6)

To a solution of the 20-azido compound 7-5 (57 mg, 0.097 mmoles) in 9:1THF: water (1.5 mL) was added polystyrene-bound triphenyl phosphine(2.19 mmole/g, 219 mg). The suspension was agitated at room temperaturefor 18 hours. The beads were removed by filtration and washed withdichloromethane, methanol, and dichloromethane. The filtrate wasconcentrated and purified by reverse-phase HPLC to afford 7-6 and itsdiastereoisomer 258 as a white solids. MS calculated M+H: 437, found437.

Examples 254-257 and 259 in Table 7a and Table 7b was prepared in asimilar manner as Example 253 and 258, but using the appropriate amineto generate the carboxamide and separation of the diastereoisomers.TABLE 7a

Mass spectrum Ex. NR²R³ Name Measured [M + H] 243

N-(pyridin-4-yl)-20-amino-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 437.6 244

N-(4,5-dimethyl-1,3-thiazol-2-yl)- 20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 471.7 245

N-(5-methylpyridin-2-yl)-20- amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 451.6 246

N-(6-methylpyridin-2-yl)-20- amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 451.6 247

N-(3-carboxamidophenyl)-20- amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 479.6

TABLE 7a

Mass spectrum Measured Ex. NR²R³ Name [M + H] 248

N-(pyridin-4-yl)-20-amino-4- methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 437.6 249

N-(6-methylpyridin-2-yl)-20- hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide 451.6

Example 250

Pharmaceutical Composition

As a specific embodiment of this invention, 100 mg ofN-[5-(isopropoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17βacetamide,is formulated with suffiecient finely divided lactose to provide a totalamount of 580 to 590 mg to fill a size 0, hard gelatin capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, it isunderstood that the practice of the invention encompasses all of theusual variations, adoptions, or modifications, as being within the scopeof the following claims and their equivalents.

Assays

In Vitro and In Vivo Assays for SARM Activity Identification ofCompounds

The compounds exemplified in the present application exhibited activityin one or more of the following assays.

Hydroxylapatite-Based Radioligand Displacement

Assay of Compound Affinity for Endogenously Expressed AR

Materials:

Binding Buffer. TEGM (10 mM Tris-HCl, 1 mM EDTA, 10% glycerol, 1 mMbeta-mecaptoethanol, 10 mM Sodium Molybdate, pH 7.2)

50% HAP Slurry: Calbiochem Hydroxylapatite, Fast Flow, in 10 mM Tris, pH8.0 and 1 mM EDTA.

Wash Buffer: 40 mM Tris, pH7.5, 100 mM KCl, 1 mM EDTA and 1 mM EGTA. 95%EtOH

Methyltrienolone, [17α-methyl-³H], (R1881*); NEN NET590

Methyltrienolone (R1881), NEN NLP005 (dissolve in 95% EtOH)

Dihydrotestosterone (DHT) [1,2,4,5,6,7-³H(N)] NEN NET453

Hydroxylapatite Fast Flow; Calbiochem Cat#391947

Molybdate=Molybdic Acid (Sigma, M1651)

MDA-MB453 Cell Culture Media: In 500 mL of complete media Final conc.RPMI 1640 (Gibco 11835-055) w/23.8 mM NaHCO₃, 2 mM L-glutamine 10 mL (1MHepes) 20 mM 5 mL (200 mM L-glu)  4 mM 0.5 mL (10 mg/mL human insulin)10 μg/mL in 0.01 N HCl Calbiochem#407694-S) 50 mL FBS (Sigma F2442) 10%1 mL (10 mg/mL Gentamicin 20 μg/mL Gibco#15710-072)Cell Passaging

Cells (Hall R. E., et al., European Journal of Cancer, 30A: 484-490(1994)) are rinsed twice in PBS, phenol red-free Trypsin-EDTA is dilutedin the same PBS 1:10. The cell layers are rinsed with 1× Trypsin, extraTrypsin is poured out, and the cell layers are incubated at 37° C. for˜2 min. The flask is tapped and checked for signs of cell detachment.Once the cells begin to slide off the flask, the complete media is addedto kill the trypsin. The cells are counted at this point, then dilutedto the appropriate concentration and split into flasks or dishes forfurther culturing (Usually 1:3 to 1:6 dilution).

Preparation of MDA-MB453 Cell Lysate

When the MDA cells are 70 to 85% confluent, they are detached asdescribed above, and collected by centrifuging at 1000 g for 10 minutesat 4° C. The cell pellet is washed twice with TEGM (10 mM Tris-HCl, 1 mMEDTA, 10% glycerol, 1 mM beta-mercaptoethanol, 10 mM Sodium Molybdate,pH 7.2). After the final wash, the cells are resuspended in TEGM at aconcentration of 10⁷ cells/mL. The cell suspension is snap frozen inliquid nitrogen or ethanol/dry ice bath and transferred to −80° C.freezer on dry ice. Before setting up the binding assay, the frozensamples are left on ice-water to just thaw (˜1 hr). Then the samples arecentrifuged at 12,500 g to 20,000 g for 30 min at 4° C. The supernatantis used to set-up assay right away. If using 50 μL of supernatant, thetest compound can be prepared in 50 μL of the TEGM buffer.

Procedure for Multiple Compound Screening

1×TEGM buffer is prepared, and the isotope-containing assay mixture isprepared in the following order: EtOH (2% final concentration inreaction), ³H-R1881 or ³H-DHT (0.5 nM final Conc. in reaction) and1×TEGM. [eg. For 100 samples, 200 μL (100×2) of EtOH+4.25 μL of 1:10³H-R1881 stock+2300 μL (100×23) 1×TEGM]. The compound is seriallydiluted, e.g., if starting final conc. is 1 μM, and the compound is in25 μL of solution, for duplicate samples, 75 μL of 4×1 μM solution ismade and 3 μL of 100 μM is added to 72 μL of buffer, and 1:5 serialdilution.

25 μL of ³H-R1881 trace and 25 μL compound solution are first mixedtogether, followed by addition of 50 μL receptor solution. The reactionis gently mixed, spun briefly at about 200 rpm and incubated at 4° C.overnight 100 μL of 50% HAP slurry is prepared and added to theincubated reaction which is then vortexed and incubated on ice for 5 to10 minutes. The reaction mixture is vortexed twice more to resuspend HAPwhile incubating reaction. The samples in 96-well format are then washedin wash buffer using The FilterMate™ Universal Harvester plate washer(Packard). The washing process transfers HAP pellet containingligand-bound expressed receptor to Unifilter-96 GF/B filter plate(Packard). The HAP pellet on the filter plate is incubated with 50 μL ofMICROSCINT (Packard) scintillint for 30 minutes before being counted onthe TopCount microscintillation counter Packard). IC₅₀s are calculatedusing R1881 as a reference.

The compounds, Examples 1-150, found in Tables 1-5, were tested in theabove assay and found to have an IC₅₀ value of 1 micromolar or less.

MMP1 Promoter Suppression, Transient Transfection Assay (TRAMPS)

HepG2 cells are cultured in phenol red free MEM containing 10%charcoal-treated FCS at 37° C. with 5% CO₂. For transfection, cells areplated at 10,000 cells/well in 96 well white, clear bottom plates.Twenty four hours later, cells are co-transfected with a MMP1promoter-luciferase reporter construct and a rhesus monkey expressionconstruct (50:1 ratio) using FuGENE6 transfection reagent, following theprotocol recommended by manufacturer. The MMP1 promoter-luciferasereporter construct is generated by insertion of a human MMP1 promoterfragment (−179/+63) into pGL2 luciferase reporter construct (Promega)and a rhesus monkey AR expression construct is generated in a CMV-Tag2Bexpression vector (Stratagene). Cells are further cultured for 24 hoursand then treated with test compounds in the presence of 100 nMphorbol-12-myristate-13-acetate (PMA), used to increase the basalactivity of MMP1 promoter. The compounds are added at this point, at arange of 1000 nM to 0.03 nM, 10 dilutions, at a concentration on 10×,1/10th volume (example: 10 microliters of ligand at 10× added to 100microliters of media already in the well). Cells are further culturedfor an additional 48 hours. Cells are then washed twice with PBS andlysed by adding 70 μL of Lysis Buffer (1×, Promega) to the wells. Theluciferase activity is measured in a 96-well format using a 1450Microbeta Jet (Perkin Elmer) luminometer. Activity of test compounds ispresented as suppression of luciferase signal from the PMA-stimulatedcontrol levels. EC₅₀ and Emax values are reported. Tissue selectiveandrogen receptor modulators of the present invention activaterepression typically with submicromolar EC₅₀ values and Emax valuesgreater than about 50%.

See Newberry E P, Willis D, Latifi T, Boudreaux J M, Towler D A,“Fibroblast growth factor receptor signaling activates the humaninterstitial coilagenase promoter via the bipartite Ets-AP1 element,”Mol. Endocrinol. 11: 1129-44 (1997) and Schneikert J, Peterziel H,Defossez P A, Klocker H, Launoit Y, Cato A C, “Androgen receptor-Etsprotein interaction is a novel mechanism for steroid hormone-mediateddown-modulation of matrix metalloproteinase expression,” J. Biol. Chem.271: 23907-23913 (1996).

Mammalian Two-Hybrid Assay for the Ligand-Induced Interaction ofN-Terminus and C-Terminus Domains of the Androgen Receptor (AgonistMode)

This assay assesses the ability of AR agonists to induce the interactionbetween the N-terminal domain (NTD) and C-terminal domain (CTD) of rhARthat reflects the in vivo virilizing potential mediated by activatedandrogen receptors. The interaction of NID and CTD of rhAR is quantifiedas ligand induced association between a Gal4 DBD-rhARCTD fusion proteinand a VP16-rhARNTD fusion protein as a mammalian two-hybrid assay inCV-1 monkey kidney cells.

The day before transfection, CV-1 cells are trypsinized and counted, andthen plated at 20,000 cells/well in 96-well plates or larger plates(scaled up accordingly) in DMEM+10% FCS. The next morning, CV-1 cellsare cotransfected with pCBB1 (Gal4 DBD-rhARLBD fusion constructexpressed under the SV40 early promoter), pCBB2 (VP16-rhAR NTD fusionconstruct expressed under the SV40 early promoter) and pFR (Gal4responsive luciferase reporter, Promega) using LIPOFECTAMINE PLUSreagent (GIBCO-BRL) following the procedure recommended by the vendor.Briefly, DNA admixture of 0.05 μg pCBB 1, 0.05 μg pCBB2 and 0.1 μg ofpFR is mixed in 3.4 μL OPTI-MEM (GIBCO-BRL) mixed with “PLUS Reagent”(1.6 μL, GIBCO-BRL) and incubated at room temperature (RT) for 15 min toform the pre-complexed DNA.

For each well, 0.4 μL LIPOFECTAMINE Reagent (GIBCO-BRL) is diluted into4.6 μL OPTI-MEM in a second tube and mixed to form the dilutedLIPOFECTAMINE Reagent. The pre-complexed DNA (above) and the dilutedLIPOFECTAMINE Reagent (above) are combined, mixed and incubated for 15minutes at room temperature. The medium on the cells is replaced with 40μL/well OPTI-MEM, and 10 μL DNA-lipid complexes are added to each well.The complexes are mixed into the medium gently and incubated at 37° C.at 5% CO₂ for 5 hours. Following incubation, 200 μL/well D-MEM and 13%charcoal-stripped FCS are added, followed by incubation at 37° C. at 5%CO₂. After 24 hours, the test compounds are added at the desiredconcentration(s) (1 nM-10 μM). Forty eight hours later, luciferaseactivity is measured using LUC-Screen system (TROPIX) following themanufacturer's protocol. The assay is conducted directly in the wells bysequential addition of 50 μL each of assay solution 1 followed by assaysolution 2. After incubation for 40 minutes at room temperature,luminescence is directly measured with 2-5 second integration.

Activity of test compounds is calculated as the E_(max) relative to theactivity obtained with 3 nM R1881. Typical tissue-selective androgenreceptor modulators of the present invention display weak or no agonistactivity in this assay with less than 50% agonist activity at 10micromolar.

See He B, Kemppainen J A, Voegel J J, Gronemeyer H, Wilson E M,“Activation function in the human androgen receptor ligand bindingdomain mediates inter-domain communication with the NH(2)-terminaldomain,” J. Biol. Chem. 274: 37219-37225 (1999).

A Mammalian Two-Hybrid Assay For Inhibition of Interaction betweenN-Terminus and C-Terminus Domains of Androgen Receptor (Antagonist Mode)

This assay assesses the ability of test compounds to antagonize thestimulatory effects of R1881 on the interaction between NTD and CTD ofrhAR in a mammalian two-hybrid assay in CV-1 cells as described above.

Forty eight hours after transfection, CV-1 cells are treated with testcompounds, typically at 10 μM, 3.3 μM, 1 μM, 0.33 μM, 100 nM, 33 nM, 10nM, 3.3 nM and 1 nM final concentrations. After incubation at 37° C. at5% CO₂ for 10-30 minutes, an AR agonist methyltrienolone (R1881) isadded to a final concentration of 0.3 nM and incubated at 37° C.Forty-eight hours later, luciferase activity is measured usingLUC-Screen system (TROPIX) following the protocol recommended by themanufacturer. The ability of test compounds to antagonize the action ofR1881 is calculated as the relative luminescence compared to the valuewith 0.3 nM R1881 alone.

Trans-Activation Modulation of Androgen Receptor (TAMAR)

This assay assesses the ability of test compounds to controltranscription from the MMTV-LUC reporter gene in MDA-M1453 cells, ahuman breast cancer cell line that naturally expresses the human AR. Theassay measures induction of a modified MMTV LTR/promoter linked to theLUC reporter gene.

20,000 to 30,000 cells/well are plated in a white, clear-bottom 96-wellplate in “Exponential Growth Medium” which consists of phenol red-freeRPMI 1640 containing 10% FBS, 4 mM L-glutamine, 20 mM HEPES, 10 ug/mLhuman insulin, and 20 ug/mL gentamicin. Incubator conditions are 37° C.and 5% CO₂. The transfection is done in batch mode. The cells aretrypsinized and counted to the right cell number in the proper amount offresh media, and then gently mixed with the Fugene/DNA cocktail mix andplated onto the 96-well plate. All the wells receive 200 TI ofmedium+lipid/DNA complex and are then incubated at 37° C. overnight. Thetransfection cocktail consists of serum-free Optimem, Fugene6 reagentand DNA. The manufacturer's (Roche Biochemical) protocol for cocktailsetup is followed.

The lipid (11) to DNA (Tg) ratio is approximately 3:2 and the incubationtime is 20 minutes at room temperature. Sixteen to 24 hrs aftertransfection, the cells are treated with test compounds such that thefinal DMSO (vehicle) concentration is <3%. The cells are exposed to thetest compounds for 48 hours. After 48 hours, the cells are lysed by aPromega cell culture lysis buffer for 30-60 minutes and then theluciferase activity in the extracts is assayed in the 96-well formatluminometer.

Activity of test compounds is calculated as the Emax relative to theactivity obtained with 100 nM R1881.

See R. E. Hall, et al., “MDA-MB-453, an androgen-responsive human breastcarcinoma cell line with high androgen receptor expression,” Eur. J.Cancer, 30A: 484-490 (1994) and R. E. Hall, et al., “Regulation ofandrogen receptor gene expression by steroids and retinoic acid in humanbreast-cancer cells,” Int J. Cancer., 52: 778-784 (1992).

In Vivo Prostate Assay

Male Sprague-Dawley rats aged 9-10 weeks, the earliest age of sexualmaturity, are used in prevention mode. The goal is to measure the degreeto which androgen-like compounds delay the rapid deterioration (˜−85%)of the ventral prostate gland and seminal vesicles that occurs during aseven day period after removal of the testes (orchiectomy [ORX]).

Rats are orchiectomized (ORX). Each rat is weighed, then anesthetized byisoflurane gas that is maintained to effect. A 1.5 cm anteroposteriorincision is made in the scrotum. The right testicle is exteriorized. Thespermatic artery and vas deferens are ligated with 4.0 silk 0.5 cmproximal to the testicle. The testicle is freed by one cut of a smallsurgical scissors distal to the ligation site. The tissue stump isreturned to the scrotum. The same is repeated for the left testicle.When both stumps are returned to the scrotum, the scrotum and overlyingskin are sutured closed with 4.0 silk. For Sham-ORX, all proceduresexcepting ligation and scissors cutting are completed. The rats fullyrecover consciousness and full mobility within 10-15 minutes.

A dose of test compound is administered subcutaneously or orally to therat immediately after the surgical incision is sutured. Treatmentcontinues for an additional six consecutive days.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 ml whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofORX. Next, the ventral portion of the prostate gland is located andblunt dissected free in a highly stylized fashion. The ventral prostateis blotted dry for 3-5 seconds and then weighed (VPW). Finally, theseminal vesicle is located and dissected free. The ventral seminalvesicle is blotted dry for 3-5 seconds and then weighed (SVWT).

Primary data for this assay are the weights of the ventral prostate andseminal vesicle. Secondary data include serum LH (luteinizing hormone)and FSH (follicle stimulating hormone), and possible serum markers ofbone formation and virilization. Data are analyzed by ANOVA plus FisherPLSD post-hoc test to identify intergroupi differences. The extent towhich test compounds inhibit ORX-induced loss of VPW and SVWT isassessed.

In Vivo Bone Formation Assay:

Female Sprague-Dawley rats aged 7-10 months are used in treatment modeto simulate adult human females. The rats have been ovariectomized (OVX)75-180 days previously, to cause bone loss and simulate estrogendeficient, osteopenic adult human females. Pre-treatment with a low doseof a powerful anti-resorptive, alendronate (0.0028 mpk SC, 2×/wk) isbegun on Day 0. On Day 15, treatment with test compound is started. Testcompound treatment occurs on Days 15-31 with necropsy on Day 32. Thegoal is to measure the extent to which androgen-like compounds increasethe amount of bone formation, shown by increased fluorochrome labeling,at the periosteal surface.

In a typical assay, nine groups of seven rats each are studied.

On Days 19 and 29 (fifth and fifteenth days of treatment), a singlesubcutaneous injection of calcein (8 mg/kg) is given to each rat.

Necropsy and Endpoints

The rat is first weighed, then anesthetized in a CO₂ chamber until neardeath. Approximately 5 mL whole blood is obtained by cardiac puncture.The rat is then examined for certain signs of death and completeness ofOVX. First, the uterus is located, blunt dissected free in a highlystylized fashion, blotted dry for 3-5 seconds and then weighed (UW). Theuterus is placed in 10% neutral-buffered formalin. Next, the right legis disarticulated at the hip. The femur and tibia are separated at theknee, substantially defleshed, and then placed in 70% ethanol.

A 1-cm segment of the central right femur, with the femoralproximal-distal midpoint ats center, is placed in a scintillation vialand dehydrated and defatted in graded alcohols and acetone, thenintroduced to solutions with increasing concentrations of methylmethacrylate. It is embedded in a mixture of 90% methyl methacrylate:10% dibutyl phthalate, that is allowed to polymerize over a 48-72 hoursperiod. The bottle is cracked and the plastic block is trimmed into ashape that conveniently fits the vice-like specimen holder of a Leica1600 Saw Microtome, with the long axis of the bone prepared forcross-sectioning. Three cross-sections of 85 cm thickness are preparedand mounted on glass slides. One section from each rat that approximatesthe midpoint of the bone is selected and blind-coded. The periostealsurface of each section is assessed for total periosteal surface, singlefluorochrome label, double fluorochrome label, and interlabel distance.

Primary data for this assay are the percentage of periosteal surfacebearing double label and the mineral apposition rate (interlabeldistance(μm)/10d), semi-independent markers of bone formation. Secondarydata include uterus weight and histologic features. Tertiary endpointscan include serum markers of bone formation and virilization. Data areanalyzed by ANOVA plus Fisher PLSD post-hoc test to identify intergroupdifferences. The extent to which test compounds increase bone formationendpoint are assessed.

1. A compound of structural formula I:

a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: Xis hydrogen, or halogen; R¹ is hydrogen, CF₃, carbonyl C₁₋₃ alkyl, C₁₋₄alkoxy, halogen, C₁₋₃ alkyl, (C₀₋₆ alkyl)₂amino C₀₋₆alkyl, andhydroxymethyl, wherein said alkyl, and alkoxy are optionally substitutedwith one to seven fluorine atoms;

 represents a group chosen from: a 5- or 6-membered monocyclic aromaticring system having 0, 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of N, O, and S, and a 9- to 14-membered polycyclic ringsystem, wherein one or more of the rings is aromatic, and wherein thepolycyclic ring system has 0, 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of N, O, and S; R² and R³ are each independently chosenfrom: hydrogen, halogen, C₁₋₈ alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkoxy C₀₋₆alkyl,hydroxycarbonyl C₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl,hydroxycarbonyl C₁₋₆ alkyloxy, hydroxy C₀₋₆alkyl, cyano,perfluoroC₁₋₄alkyl, perfluoroC₁₋₄alkoxy, C₀₋₆ alkylcarbonyl, C₁₋₆alkylcarbonyloxy, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, C₁₋₆alkoxycarbonylamino, C₁₋₆alkylaminocarbonylamino, (C₁₋₆alkyl)₂aminocarbonylamino, and (C₁₋₆alkyl)₂ aminocarbonyloxy, wherein R² and R³together with the carbon atom to which they are attached can optionallyform a spiro-C₃₋₄ cycloalkyl group, or an oxo group; R² and R³ are eachindependently optionally substituted with one or more R⁸; R⁴, R⁵, R⁶,and R⁷ are each independently chosen from: hydrogen, halogen,(carbonyl)₀₋₁C₁₋₁₀ alkyl, (carbonyl)₀₋₁C₂₋₁₀ alkenyl, (carbonyl)₀₋₁C₂₋₁₀alkynyl, (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀alkyl(carbonyl)₀₋₁, (C₃₋₈)heterocyclyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,C₁₋₄acylamino C₀₋₁₀ alkyl, C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₀₋₁₀alkylamino C₀₋₁₀ alkylaminocarbonyl, di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl,arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl, (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylamino C₀₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,(C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀alkyl aminocarbonylamino, (C₁₋₁₀ alkyl)₂aminocarbonylamino, (aryl C₁₋₁₀alkyl)₁₋₂aminocarbonylamino, C₀₋₁₀ alkyl aminocarbonylamino, C₃₋₈heterocyclyl C₀₋₁₀ alkyl aminocarbonylamino, (C₀₋₁₀ alkyl)₂aminocarbonylC₀₋₁₀ alkyl, (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl, C₀₋₁₀ alkylaminocarbonyl C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonylC₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,aryl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₂aminocarbonyl,(aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl, C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀alkyl, C₀₋₁₀ alkyl carbonylamino(C₀₋₁₀ alkyl), C₀₋₁₀ alkoxycarbonylamino(C₀₋₁₀ alkyl), carboxy C₀₋₁₀ alkylamino, carboxy C₀₋₁₀alkyl, carboxy aryl, carboxy C₃₋₈ cycloalkyl, carboxy C₃₋₈ heterocyclyl,C₁₋₁₀ alkoxy, C₁₋₁₀ alkyloxy C₀₋₁₀alkyl, C₁₀ alkylcarbonyloxy, C₃₋₈heterocyclyl C₀₋₁₀ alkylcarbonyloxy, C₃₋₈ cycloalkyl C₀₋₁₀alkylcarbonyloxy, aryl C₀₋₁₀ alkylcarbonyloxy, C₁₋₁₀ alkylcarbonyloxyamino, C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy amino, C₃₋₈ cycloalkylC₀₋₁₀ alkylcarbonyloxy amino, aryl C₀₋₁₀ alkylcarbonyloxy amino, (C₁₋₁₀alkyl)₂aminocarbonyloxy, (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy, (C₃₋₈heterocyclyl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy, (C₃₋₈ cycloalkylC₀₋₁₀alkyl)₁₋₂aminocarbonyloxy, hydroxy C₀₋₁₀alkyl,hydroxycarbonylC₀₋₁₀alkoxy, hydroxycarbonylC₀₋₁₀alkyloxy, C₁₋₁₀alkylthio, C₁₋₁₀ alkylsulfinyl, aryl C₀₋₁₀ alkylsulfinyl, C₃₋₈heterocyclyl C₀₋₁₀ alkylsulfinyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfinyl,C₁₋₁₀ alkylsulfonyl, aryl C₀₋₁₀ alkylsulfonyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylsulfonyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfonyl, C₁₋₁₀alkylsulfonylamino, aryl C₁₋₁₀ alkylsulfonylamino, C₃₋₈ heterocyclylC₁₋₁₀ alkylsulfonylamino, C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,cyano, nitro, perfluoroC₁₋₆alkyl, and perfluoroC₁₋₆alkoxy; wherein R⁴,R⁵, R⁶, and R⁷ are each independently optionally substituted with one ormore R⁸; R⁸ is chosen from: hydrogen, halogen, (carbonyl)₀₋₁C₁₋₁₀ alkyl,(carbonyl)₀₋₁C₂₋₁₀ alkenyl, (carbonyl)₀₋₁C₂₋₁₀ alkynyl,(carbonyl)₀₋₁aryl C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl,(C₃₋₈)heterocyclyl C₀₋₁₀ alkyl, C₁₋₄acylamino C₀₋₁₀ alkyl, C₀₋₁₀alkylamino C₀₋₁₀ alkyl, di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl, arylC₀₋₁₀alkylamino C₀₋₁₀ alkyl, (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylamino C₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₂aminocarbonyl, C₁₋₁₀ alkoxy(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀alkyloxy C₀₋₁₀alkyl, (C₁₋₁₀alkyl)₂aminocarbonyloxy, hydroxycarbonylC₀₋₁₀alkoxy, (C₁₋₁₀alkyl)₂aminocarbonyloxy, (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy, hydroxyC₀₋₁₀alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ alkylsulfonylamino, aryl C₁₋₁₀alkylsulfonylamino, C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino, C₃₋₈cycloalkyl C₁₋₁₀ alkylsulfonylamino, cyano, nitro, perfluoroC₁₋₆alkyl,and perfluoroC₁₋₆alkoxy, R⁸ is optionally substituted with one or moregroups selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN,O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and provided that when

 is pyridinyl and R² is methyl then R³ is other than hydrogen.
 2. Acompound according to claim 1, wherein

is chosen from phenyl, naphthinyl, benzimidazolyl, benzofuranyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzodihydrofuranyl,1,3-benzodioxilyl, 2,3-dihydro-1,4-benzodioxinyl, quinoxalinyl,quinolizinyl, quinazolinyl, indazolyl, quinolyl, isoquinolyl, furanyl,thienyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, oxidopyridyl,isothiazolyl, isoindolyl, pyrazolyl, pyrrolyl, 1,6-dihydropyridinyl,pyridinyl, pyrimidinyl, pyrazinyl, pyrrolinyl, pyrazolinyl,thiadiazolyl, oxadiazolyl, tetrazolyl, and triazolyl.
 3. A compoundaccording to claim 2, wherein

is chosen from phenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl,quinoxalinyl, oxidopyridyl, quinolizinyl, quinazolinyl, quinolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, 1,6-dihydropyridinyl,pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl, and thiadiazolyl.
 4. Acompound according to claim 3, wherein

is chosen from phenyl, pyridinyl, pyrimidinyl, pyrazinyl, tetrazolyl,and thiazolyl.
 5. A compound according to claim 4, wherein

is chosen from pyridinyl and pyrimidinyl.
 6. A compound according toclaim 5, wherein

is chosen from phenyl, pyrazinyl, tetrazolyl, and thiazolyl.
 7. Acompound of structural formula I:

a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: Xis hydrogen, or halogen; R¹ is hydrogen, CF₃, halogen, C₁₋₃ alkyl, (C₀₋₆alkyl)₂amino C₀₋₆alkyl, and hydroxymethyl, wherein said alkyl, andalkoxy are optionally substituted with one to seven fluorine atoms;

 represents a group chosen from: phenyl, naphthinyl, benzimidazolyl,benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl,benzodihydrofuranyl, quinoxalinyl, quinolizinyl, quinazolinyl,1,3-benzodioxilyl, 2,3-dihydro-1,4-benzodioxinyl, indolyl, indazolyl,quinolyl, isoquinolyl, furanyl, thienyl, imidazolyl, oxazolyl,thiazolyl, isoxazolyl, isothiazolyl, isoindolyl, oxidopyridyl,pyrazolyl, pyrrolyl, 1,6-dihydropyridinyl, pyridinyl, pyrimidinyl,pyrazinyl, pyrrolinyl, pyrazolinyl, thiadiazolyl, oxadiazolyl,tetrazolyl, and triazolyl; R² and R³ are each independently chosen from:hydrogen, halogen, C₁₋₈ alkyl, amino C₀₋₆alkyl, C₁₋₆ alkylaminoC₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, (C₀₋₆alkyl)amino, (C₀₋₆alkyl)carbonylamino, C₁₋₆ alkoxy C₀₋₆alkyl, hydroxycarbonyl C₀₋₆alkyl, C₁₋₆alkoxycarbonyl C₀₋₆alkyl, hydroxycarbonyl C₁₋₆ alkyloxy, hydroxyC₀₋₆alkyl, cyano, perfluoroC₁₋₄alkyl, and perfluoroC₁₋₄alkoxy, whereinR² and R³ together with the carbon atom to which they are attached canoptionally form a spiro-C₃₋₆ cycloalkyl group, or an oxo group, R² andR³ are each independently optionally substituted with one or more R⁸;R⁴, R⁵, R⁶, and R⁷ are each independently chosen from: hydrogen,halogen, (carbonyl)₀₋₁C₁₋₁₀ alkyl, (carbonyl)₀₋₁C₂₋₁₀ alkenyl,(carbonyl)₀₋₁C₂₋₁₀ alkynyl, (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁, (C₃₋₈)heterocyclyl C₀₋₁₀alkyl(carbonyl)₀₋₁, C₁₋₄acylamino C₀₋₁₀ alkyl, C₀₋₁₀ alkylamino C₀₋₁₀alkyl, C₀₋₁₀ alkylamino C₀₋₁₀ alkylaminocarbonyl, di-(C₁₋₁₀ alkyl)aminoC₀₋₁₀ alkyl, arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl, (arylC₀₋₁₀ alkyl)₂aminoC₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₃₋₈heterocyclyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀alkyl)₂amino C₀₋₁₀ alkyl, (C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonylamino, (C₁₋₁₀alkyl)₂aminocarbonylamino, (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonylamino,C₀₋₁₀ alkyl aminocarbonylamino, C₃₋₈ heterocyclyl C₀₋₁₀ alkylaminocarbonylamino, (C₁₋₁₀ alkyl)₂aminocarbonyl C₀₋₁₀ alkyl, (aryl C₁₋₁₀alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl, C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, C₃₋₈heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, aryl C₀₋₁₀ alkylaminocarbonyl C₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₂aminocarbonyl, (aryl C₁₋₁₀alkyl)₁₋₂aminocarbonyl, C₁₋₁₀ alkoxy (carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀alkyl carbonylamino(C₀₋₁₀ alkyl), C₀₋₁₀ alkoxy carbonylamino(C₀₋₁₀alkyl), carboxy C₀₋₁₀ alkylamino, carboxy C₀₋₁₀ alkyl, carboxy aryl,carboxy C₃₋₈ cycloalkyl, carboxy C₃₋₈ heterocyclyl, C₁₋₁₀ alkoxy,C₁₋₁₀alkyloxy C₀₋₁₀alkyl, C₁₋₁₀ alkylcarbonyloxy, C₃₋₈ heterocyclylC₀₋₁₀ alkylcarbonyloxy, C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy, arylC₀₋₁₀ alkylcarbonyloxy, C₁₋₁₀ alkylcarbonyloxy amino, C₃₋₈ heterocyclylC₀₋₁₀ alkylcarbonyloxy amino, C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxyamino, aryl C₀₋₁₀ alkylcarbonyloxy amino, (C₁₋₁₀alkyl)₂aminocarbonyloxy, (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy, (C₃₋₈heterocyclyl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy, (C₃₋₈ cycloalkylC₀₋₁₀alkyl)₁₋₂aminocarbonyloxy, hydroxy C₀₋₁₀alkyl,hydroxycarbonylC₀₋₁₀alkoxy, hydroxycarbonylC₀₋₁₀alkyloxy, C₁₋₁₀alkylthio, C₁₋₁₀ alkylsulfinyl, aryl C₀₋₁₀ alkylsulfinyl, C₃₋₈heterocyclyl C₀₋₁₀ alkylsulfinyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfinyl,C₁₋₁₀ alkylsulfonyl, aryl C₀₋₁₀ alkylsulfonyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylsulfonyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfonyl, C₁₋₁₀alkylsulfonylamino, aryl C₁₋₁₀ alkylsulfonylamino, C₃₋₈ heterocyclylC₁₋₁₀ alkylsulfonylamino, C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,cyano, nitro, perfluoroC₁₋₆alkyl, and perfluoroC₁₋₆alkoxy; wherein R⁴,R⁵, R⁶, and R⁷ are each independently optionally substituted with one ormore R⁸; and R⁸ is chosen from: hydrogen, halogen, (carbonyl)₀₋₁C₁₋₁₀alkyl, (carbonyl)₀₋₁C₂₋₁₀ alkenyl, (carbonyl)₀₋₁C₂₋₁₀ alkynyl,(carbonyl)₀₋₁aryl C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl,(C₃₋₈)heterocyclyl C₀₋₁₀ alkyl, C₁₋₄acylamino C₀₋₁₀ alkyl, C₀₋₁₀alkylamino C₀₋₁₀ alkyl, di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl, arylC₀₋₁₀alkylamino C₀₋₁₀ alkyl, (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylamino C₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₂aminocarbonyl, C₁₋₁₀ alkoxy(carbonyl)₀₁C₀₋₁₀ alkyl, C₁₋₁₀alkyloxy C₀₋₁₀alkyl, (C₁₋₁₀alkyl)₂aminocarbonyloxy, hydroxycarbonylC₀₋₁₀alkoxy, (C₁₋₁₀alkyl)₂aminocarbonyloxy, (aryl C₀₋₁₀ alkyl)₁₋₂aminocarbonyloxy, hydroxyC₀₋₁₀alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀ alkylsulfonylamino, aryl C₁₋₁₀alkylsulfonylamino, C₃₋₈ heterocyclyl C₁₋₁₀ alkylsulfonylamino, C₃₋₈cycloalkyl C₁₋₁₀ alkylsulfonylamino, cyano, nitro, perfluoroC₁₋₆alkyl,and perfluoroC₁₋₆alkoxy, wherein R⁸ is optionally substituted with oneor more groups selected from hydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H,CN, O(C═O)C₁-C₆ alkyl, NO₂, trifluoromethoxy, trifluoroethoxy,—O_(b)(C₁₋₁₀)perfluoroalkyl, and NH₂; and provided that when

 is pyridinyl and R² is methyl then R³ is other than hydrogen.
 8. Acompound according to claim 7, wherein X is halogen.
 9. A compoundaccording to claim 7, wherein X is hydrogen.
 10. A compound according toclaim 9, wherein R¹ is methyl.
 11. A compound according to claim 2,wherein:

a pharmaceutically acceptable salt or a stereoisomer thereof, wherein: Xis hydrogen or halogen; R¹ is hydrogen, CF₃, halogen, C₁₋₃ alkyl, (C₀₋₆alkyl)₂amino C₀₋₆alkyl, and hydroxymethyl, wherein said alkyl, andalkoxy are optionally substituted with one to seven fluorine atoms;

 represents a group chosen from: phenyl, pyridinyl, and pyrimidinyl; R²and R³ are each independently chosen from: hydrogen, halogen, C₁₋₈alkyl, (C₀₋₆alkyl)amino, (C₀₋₆alkyl) carbonylamino, amino C₀₋₆alkyl,C₁₋₆ alkylamino C₀₋₆alkyl, (C₁₋₆ alkyl)₂amino C₀₋₆alkyl, C₁₋₆ alkoxyC₀₋₆alkyl, C₁₋₆ alkoxycarbonyl C₀₋₆alkyl, hydroxy C₀₋₆alkyl, cyano,perfluoroC₁₋₄alkyl, and perfluoroC₁₋₄alkoxy, wherein R² and R³ togetherwith the carbon atom to which they are attached can optionally form aspiro-C₃₋₆cycloalkyl group, or an oxo group, R² and R³ are eachindependently optionally substituted with one or more R⁸; R⁴ is chosenfrom: hydrogen, (carbonyl)₀₋₁C₁₋₁₀ alkyl, (carbonyl)₀₋₁aryl C₁₋₁₀ alkyl,C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁, (C₃₋₈)heterocyclyl C₀₋₁₀alkyl(carbonyl)₀₋₁, C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, carboxy C₀₋₁₀ alkyl,carboxy aryl, carboxy C₃₋₈ cycloalkyl, carboxy C₃₋₈ heterocyclyl,C₁₋₁₀alkyloxy C₀₋₁₀alkyl, hydroxy C₀₋₁₀alkyl, and perfluoroC₁₋₆alkyl,wherein R⁴ is optionally substituted with one or more R⁸; R⁵, R⁶, and R⁷are each independently chosen from: hydrogen, halogen,(carbonyl)₀₋₁C₁₋₁₀ alkyl, (carbonyl)₀₋₁C₂₋₁₀ alkenyl, (carbonyl)₀₋₁arylC₁₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl(carbonyl)₀₋₁,(C₃₋₈)heterocyclyl C₀₋₁₀ alkyl(carbonyl)₀₋₁, C₁₋₄acylamino C₀₋₁₀ alkyl,C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₀₋₁₀ alkylamino C₀₋₁₀ alkylaminocarbonyl,di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl, arylC₀₋₁₀ alkylamino C₀₋₁₀ alkyl,C₃₋₈ cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylamino C₀₋₁₀ alkyl, (C₃₋₈ cycloalkyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl,(C₃₋₈ heterocyclyl C₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀alkyl aminocarbonylamino, (C₁₋₁₀ alkyl)₂aminocarbonylamino, (aryl C₁₋₁₀alkyl)₁₋₂aminocarbonylamino, C₀₋₁₀ alkyl aminocarbonylamino, C₃₋₈heterocyclyl C₀₋₁₀ alkyl aminocarbonylamino, (C₁₋₁₀ alkyl)₂aminocarbonylC₀₋₁₀ alkyl, (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl C₀₋₁₀ alkyl, C₀₋₁₀ alkylaminocarbonyl C₀₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl aminocarbonylC₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl,aryl C₀₋₁₀ alkyl aminocarbonyl C₀₋₁₀ alkyl, (C₁₋₁₀alkyl)₁₋₂aminocarbonyl, (aryl C₁₋₁₀ alkyl)₁₋₂aminocarbonyl, C₁₋₁₀ alkoxy(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₀₋₁₀ alkyl carbonylamino(C₀₋₁₀ alkyl), C₀₋₁₀alkoxy carbonylamino(C₀₋₁₀ alkyl), carboxy C₀₋₁₀ alkylamino, carboxyC₀₋₁₀ alkyl, carboxy aryl, carboxy C₃₋₈ cycloalkyl, carboxy C₃₋₈heterocyclyl, C₁₋₁₀ alkoxy, C₁₋₁₀alkyloxy C₀₋₁₀alkyl, C₁₋₁₀alkylcarbonyloxy, C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy, C₃₋₈cycloalkyl C₀₋₁₀ alkylcarbonyloxy, aryl C₀₋₁₀ alkylcarbonyloxy, C₁₋₁₀alkylcarbonyloxy amino, C₃₋₈ heterocyclyl C₀₋₁₀ alkylcarbonyloxy amino,C₃₋₈ cycloalkyl C₀₋₁₀ alkylcarbonyloxy amino, aryl C₀₋₁₀alkylcarbonyloxy amino, (C₁₋₁₀ alkyl)₂aminocarbonyloxy, (aryl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy, (C₃₋₈ heterocyclyl C₀₋₁₀alkyl)₁₋₂aminocarbonyloxy, (C₃₋₈ cycloalkylC₀₋₁₀alkyl)₁₋₂aminocarbonyloxy, hydroxy C₀₋₁₀alkyl,hydroxycarbonylC₀₋₁₀alkoxy, hydroxycarbonylC₀₋₁₀alkyloxy, C₁₋₁₀alkylthio, C₁₋₁₀ alkylsulfonyl, aryl C₀₋₁₀ alkylsulfonyl, C₃₋₈heterocyclyl C₀₋₁₀ alkylsulfonyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkylsulfonyl,C₁₋₁₀ alkylsulfonylamino, aryl C₁₋₁₀ alkylsulfonylamino, C₃₋₈heterocyclyl C₁₋₁₀ alkylsulfonylamino, C₃₋₈ cycloalkyl C-110alkylsulfonylamino, cyano, nitro, perfluoroC₁₋₆alkyl, andperfluoroC₁₋₆alkoxy, wherein R⁵, R⁶, and R⁷ are each independentlyoptionally substituted with one or more R⁸; R⁸ is chosen from: hydrogen,halogen, (carbonyl)₀₋₁C₁₋₁₀ alkyl, (carbonyl)₀₋₁C₂₋₁₀ alkenyl,(carbonyl)₀₋₁aryl C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl C₀₋₁₀ alkyl,(C₃₋₈)heterocyclyl C₀₋₁₀ alkyl, C₁₋₄acylamino C₀₋₁₀ alkyl, C₀₋₁₀alkylamino C₀₋₁₀ alkyl, di-(C₁₋₁₀ alkyl)amino C₀₋₁₀ alkyl, arylC₀₋₁₀alkylamino C₀₋₁₀ alkyl, (arylC₀₋₁₀ alkyl)₂amino C₀₋₁₀ alkyl, C₃₋₈cycloalkyl C₀₋₁₀ alkylamino C₀₋₁₀ alkyl, C₃₋₈ heterocyclyl C₀₋₁₀alkylamino C₀₋₁₀ alkyl, (C₁₋₁₀ alkyl)₂aminocarbonyl, C₁₋₁₀ alkoxy(carbonyl)₀₋₁C₀₋₁₀ alkyl, C₁₋₁₀alkyloxy C₀₋₁₀alkyl, (C₁₋₁₀alkyl)₂aminocarbonyloxy, hydroxycarbonylC₀₋₁₀alkoxy, (C₁₋₁₀alkyl)₂aminocarbonyloxy, hydroxy C₀₋₁₀alkyl, C₁₋₁₀ alkylsulfonyl, C₁₋₁₀alkylsulfonylamino, aryl C₁₋₁₀ alkylsulfonylamino, C₃₋₈ heterocyclylC₁₋₁₀ alkylsulfonylamino, C₃₋₈ cycloalkyl C₁₋₁₀ alkylsulfonylamino,cyano, nitro, perfluoroC₁₋₆alkyl, and perfluoroC₁₋₆alkoxy; wherein, R⁸is optionally substituted with one or more groups selected fromhydrogen, OH, (C₁₋₆)alkoxy, halogen, CO₂H, CN, O(C═O)C₁-C₆ alkyl, NO₂,trifluoromethoxy, trifluoroethoxy, —O_(b)(C₁₋₆)perfluoroalkyl, and NH₂;and provided that when

is pyridinyl and R² is methyl then R³ is other than hydrogen.
 12. Acompound according to claim 1, selected from:N-[6-(trifluoromethyl)pyridin-3-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(phenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4,5-dimethyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-chloro-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methyl-1,3-thiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-chloro-1,3-benzoxazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(quinoxalin-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyrazin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(nicotinamid-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-methyl-1,3-benzothiazol-6-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17-acetamide;N-(5-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-cyanophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-chloropyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17-acetamide;N-(6-aminopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methyl-1,2,4-thiadiazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(trifluoromethyl)pyridin-2-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-nitro-1H-imidazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-aminopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-ethyl-6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methoxy-6-methylpyrimidin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-bromo-6-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1H-benzimidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1H-pyrazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-fluoropyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4,6-dimethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1-oxidopyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-ethylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-aminopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-(acetylamino)pyridin-3-yl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(methyl5-pyridin-2-ylcarbamate)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(pyridin-5-yl)-2,2-dimethylpropanamid-2-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-(formylamino)pyridin-3-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1H-imidazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-cyanopyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methylisoxazol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-chloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-tert-butylisoxazol-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2,6-dimethoxypyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-n-17β-acetamide;N-(6-chloropyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3,5-difluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2,6-difluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[3-(trifluoromethyl)phenyl]-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[4-(trifluoromethyl)phenyl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[4-(trifluoromethoxy)phenyl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methylpyridin-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(2-carboxamidyl)pyridin-5-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-aminopyrimidin-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-aminopyrimidin-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3,5-dichloropyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methoxypyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;N-(3-methylpyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-aminopyridin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(3-trifluoromethoxy)pyridin-4-yl]4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-ethylpyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-methylquinolin-4-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-4-methylcarboxyl-phenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-aminopyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-5-fluorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-3-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-4-trifluoromethylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-4-methoxyphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-5-chlorophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-5-methylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-aminophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methyl-4-aminopyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-amino-5-trifluoromethylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-amino-4,6-dimethyl-5-chloropyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-4,6-dimethylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-amino-4-methylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyrid-2-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-methylpyrimid-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-3-methoxycarbonylphenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-carboxamidophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-carboxamidophenyl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-6-methylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2,6-diaminopyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-5-methoxycarbonyl-pyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-5-methylpyrid-3-yl)-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methylpyridin-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(4,6-dimethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(tetrazol-5-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methyl-1,2-isothiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methyl-1,2-thiazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-methyl-pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(5-trifluoromethyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(6-trifluoromethyl)-pyrid-3-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methyl-1,3-thiazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methyl-1,3-thiazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1H-indazol-6-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(imidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methylpyrazol-3-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(2,6-dimethyl)-1,3-pyrimid-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1,3-pyrazin-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methyl-1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1,3-pyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(benzimidazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(3-carboxamido)-pyridin-6-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-fluoropyrimid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyrid-4-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4,5-dimethylisoxazol-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(5-carboxyl)-pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-cyanopyrid-2-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(mopholin-4-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(piperizin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(pyrollidin-1-ylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(diamin-1-ylethylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(histaminylcarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[(2-ethylamino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[(1-hydroxymethyl)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[(2-methoxyethyl)-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[2-(piperizinyl)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[3-(morphilino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[2-(morphilino)-ethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[(3-dimethylamino)-propylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(methoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17-acetamide;N-[5-(ethoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(isopropoxycarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(5-cyano-4,6-dimethyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(5-bromo-6-methyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[methylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[N-(2-methoxyethyl)-N-methyl-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[N-(dimethylaminoethyl)-N-methyl-aminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(ethoxycarbonyl)-4-methyl-pyrimid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(6-methyl)pyrid-3-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[4-(carboxyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[4-(carboxamido)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[4-(N,N-dimethylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[(N,N-dimethylamino)ethylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[4-(N-methylaminocarbonyl)-1,3-thiazol-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(carboxamido)-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[2-(ethoxycarbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[2-(carboxamido)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[2-(carboxyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[2-(N-methylaminocarbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[2-(N,N-dimethylaminocarbonyl)-1-methyl-1H-imidazol-4-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(hydroxylaminocarbonyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(1H-tetrazol-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-aminopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(1H-pyrazol-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(pyrimidin-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-pyrimidin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(pyrazin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-(2-furyl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-bromopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-bromopyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3,3′-bipyridin-6′-yl)-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-(pyrimidin-5-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[(aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[(N-methyl-aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[(N,N-dimethyl-aminocarbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[({[2-(dimethylamino)ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[({[2-(N-piperidinyl)ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[({[2-morpholin-4-ethyl]amino}carbonyl)amino]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{4-methyl-5-[dimethylaminocarbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{6-[carboxamido]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-(pyrizin-2-yl)pyrid-2-yl]-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[(phenylsulfonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[(sulfonamido]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-sulfopyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-{5-[N-(diaminomethylene)-carbonyl]pyrid-2-yl}-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-(trifluoromethyl)pyridin-3-yl]-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-3-yl)-2-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[6-(trifluoromethyl)pyridin-3-yl]-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-chloropyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17βacetamide;N-(6-fluoropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methoxypyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-chloropyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-cyanopyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-trifluromethylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methylpyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-fluoropyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1,3-thiazol-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(1,3-pyrimid-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyrizin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-chloropyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2,6-dichloropyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-cyanopyridin-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-chloro-1,3-benzoxazol-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methylisoxazol-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(imidazol-2-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyrazol-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-carboxamidopyridin-3-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-methyl-N-(3-methylpyridin-4-yl)-20-fluoro-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-4-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-aminopyridin-3-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-[5-methylpyridin-2-yl]4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(2-amino-4-methoxycarbonyl-phenyl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-3-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-4-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-carboxamidopyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyrizin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-fluoropyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-aminopyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17α-acetamide;N-(4,5-dimethyl-1,3-thiazol-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-2-yl)-4-ethyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-4-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(4,5-dimethyl-1,3-thiazol-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(5-methylpyridin-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-2-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(3-carboxamidophenyl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(pyridin-4-yl)-20-amino-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;N-(6-methylpyridin-2-yl)-20-hydroxy-4-methyl-3-oxo-4-aza-5α-androst-1-en-17β-acetamide;and pharmaceutically acceptable salts and stereoisomers thereof. 13.(canceled)
 14. (canceled)
 15. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier.
 16. A composition of claim 15,further comprising an active ingredient selected from: 1) an estrogen oran estrogen derivative, alone or in combination with a progestin orprogestin derivative, 2) a bisphosphonate, 3) an antiestrogen or aselective estrogen receptor modulator, 4) an αvβ3 integrin receptorantagonist, 5) a cathepsin K inhibitor, 6) (f) an HMG-CoA reductaseinhibitor, 7) (g) an osteoclast vacuolar ATPase inhibitor, 8) (h) anantagonist of VEGF binding to osteoclast receptors, 9) an activator ofperoxisome proliferator-activated receptor γ, 10) calcitonin, 11) acalcium receptor antagonist, 12) parathyroid hormone or analog thereof,13) a growth hormone secretagogue, 14) human growth hormone, 15)insulin-like growth factor, 16) a p38 protein kinase inhibitor, 17) bonemorphogenetic protein, 18) an inhibitor of BMP antagonism, 19) aprostaglandin derivative, 20) vitamin D or vitamin D derivative, 21)vitamin K or vitamin K derivative, 22) ipriflavone, 23) fluoride salts,24) dietary calcium supplement, and 25) osteoprotegerin.
 17. Thecomposition according to claim 16, wherein: 1) the estrogen or estrogenderivative, alone or in combination with a progestin or progestinderivative, is selected from conjugated estrogen, equine estrogen,17β-estradiol, estrone, 17β-ethynyl estradiol, 17β-ethynyl estradiolwith at least one agent selected from norethindrone andmedroxyprogesterone acetate; 2) the bisphosphonate is selected fromalendronate, clodronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, pamidronate, piridronate,risedronate, tiludronate, and zoledronate; 3) the antiestrogen orselective estrogen receptor modulator is selected from raloxifene,clomiphene, zuclomiphene, enclomiphene, nafoxidene, CI-680, CI-628,CN-55,945-27, Mer-25, U-11,555A, U-100A, tamoxifen, lasofoxifene,toremifene, azorxifene, EM-800, EM-652, TSE 424, droloxifene, idoxifene,and levormeloxifene; 4) the HMG-CoA reductase inhibitor is selected fromlovastatin, simvastatin, dihydroxy-open acid simvastatin, pravastatin,fluvastatin, atorvastatin, cerivastatin, rosuvastatin, pitavastatin, andnisvastatin; 5) calcitonin is salmon calcitonin administered as a nasalspray; 6) bone morphogenetic protein is selected from BMP 2, BMP 3, BMP5, BMP 6, BMP 7, TGF beta, and GDF5; 7) insulin-like growth factor isselected from IGF I and IGF H alone or in combination with IGF bindingprotein 3; 8) the prostaglandin derivative is selected from agonists ofprostaglandin receptors EP₁, EP₂, EP₄, FP, and IP; 9) the fibroblastgrowth factor is selected from aFGF and bFGF; 10) parathyroid hormone(PTH) or PTH analog is selected from PTH subcutaneous injection, humanPTH (1-84), human PTH (1-34), and other partial sequences, native orwith substitutions; 11) vitamin D or vitamin D derivative is selectedfrom natural vitamin D, 25-OH-vitamin D3, 1α,25(OH)₂ vitamin D3,1α-OH-vitamin D3, 1α-OH-vitamin D2, dihydrotachysterol,26,27-F6-1α,25(OH)₂ vitamin D3,19-nor-1α,25(OH)₂ vitamin D3,22-oxacalcitriol, calcipotriol, 1α,25(OH)-2-16-ene-23-yne-vitamin D3(Ro23-7553), EB1089, 20-epi-1α,25(OH)₂ vitamin D3, KH1060, ED71,1α,24(S)—(OH)₂ vitamin D3, and 1α,24(R)—(OH)₂ vitamin D3; 12) thedietary calcium supplement is selected from calcium carbonate,calciumcitrate, and natural calcium salts; and 13) the fluoride saltsare chosen from sodium fluoride and monosodium fluorophosphate (MFP);and pharmaceutically acceptable salts or stereoisomers thereof.
 18. Thecomposition according to claim 17, wherein the bisphosphonate isalendronate monosodium trihydrate or alendronate monosodium monohydrate.19. The composition of claim 16, wherein said agent is selected from: 1)an estrogen or an estrogen derivative, alone or in combination with aprogestin or progestin derivative, 2) a bisphosphonate, 3) anantiestrogen or a selective estrogen receptor modulator, 4) an αvβ3integrin receptor antagonist, 5) a cathepsin K inhibitor, 6) anosteoclast vacuolar ATPase inhibitor, 7) calcitonin, 8) osteoprotegrin,and 9) parathyroid hormone or analog thereof.
 20. A pharmaceuticalcomposition made by combining a compound according to claim 1 and apharmaceutically acceptable carrier.
 21. A process for making apharmaceutical composition comprising combining a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 22. A method formodulating a function mediated by the androgen receptor in a mammal inneed of such modulation comprising administering a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt or a stereoisomer thereof.
 23. A method of activatingthe function of the androgen receptor in a mammal in need of suchactivation comprising administering a therapeutically effective amountof a compound of claim 1 or a pharmaceutically acceptable salt or astereoisomer thereof.
 24. A method of claim 23, wherein said functionmediated by the androgen receptor is activated in bone or muscle tissureand blocked in the prostate or the uterus.
 25. A method of treating acondition in a mammal which is caused by androgen deficiency, which canbe ameliorated by androgen replacement, or which can be increased byandrogen replacement, which condition is selected from weakened muscletone, osteoporosis, osteopenia, glucocorticoid-induced osteoporosis,periodontal disease, bone fracture, bone damage following bonereconstructive surgery, sarcopenia, frailty, aging skin, malehypogonadism, postmenopausal symptoms in women, atherosclerosis,hypercholesterolemia, hyperlipidemia, obesity, aplastic anemia,hematopoietic disorders, arthritic condition and joint repair,HIV-wasting, prostate cancer, cancer cachexia, muscular dystrophies,Alzheimer's disease, cognitive decline, sexual disfunction, sleep apnea,benign prostate hyperplasia, depression, premature ovarian failure, andautoimmune disease, comprising administering to the mammal in need ofsuch treatment, a therapeutically effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt or astereoisomer thereof.
 26. A method according to claim 25, wherein saidcondition is chosen from osteoporosis, cancer cachexia and sarcopenia.27. A method according to claim 26, wherein said condition isosteoporosis.
 28. A method of treating osteoporosis in a mammal in needthereof, comprising administering a therapeutically effective amount ofa compound according to claim 1 or a pharmaceutically acceptable salt ora stereoisomer thereof.